Chronic Care in Cardiology

Caitlin M. Gibson, Pharm.D., MEd, BCPS, BCCP

Virginia Commonwealth University School of Pharmacy
Richmond, Virginia
 Chronic Care in Cardiology

Chronic Care in Cardiology

Caitlin M. Gibson, Pharm.D., MEd, BCPS, BCCP
Virginia Commonwealth University School of Pharmacy
Richmond, Virginia

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 Chronic Care in Cardiology

Learning Objectives HDL-C High-density lipoprotein-cholesterol

HF Heart failure
1. Recommend patient-specific guideline-directed HFpEF Heart failure with preserved ejection
medical pharmacologic therapy for the manage- fraction
ment of chronic heart failure. HFrecEF Heart failure with recovered ejection
fraction
2. Develop an evidence-based pharmacologic reg-
HFrEF Heart failure with reduced ejection
imen and monitoring plan for patients with atrial
fraction
fibrillation. HFSA Heart Failure Society of America
3. Develop an optimal pharmacologic management HR Heart rate
plan for a patient with hypertension according to HRS Heart Rhythm Society
practice guidelines and clinical trial evidence. HTN Hypertension
4. Design an appropriate dyslipidemia regimen based INR International normalized ratio
on a patient’s atherosclerotic cardiovascular dis- K Potassium
ease (ASCVD) risk. LDL-C Low-density lipoprotein-cholesterol
5. Determine the appropriate pharmacologic therapy LFTs Liver function tests
for patients with stable coronary heart disease. LVEF Left ventricular ejection fraction
MI Myocardial infarction
mAb Monoclonal antibody
Abbreviations in This Chapter
MRA Mineralocorticoid receptor antagonist
Na Sodium
ACC/AHA A
 merican College of Cardiology/
American Heart Association NSAID Nonsteroidal anti-inflammatory drug
ACCP American College of Chest Physicians NSR Normal sinus rhythm
ACE Angiotensin-converting enzyme NYHA New York Heart Association
AF Atrial fibrillation P-gp P-glycoprotein
ARB Angiotensin II receptor blocker PAD Peripheral arterial disease
ARNI Angiotensin receptor-neprilysin inhibitor PCE Pooled Cohort Equation
ASCVD Atherosclerotic cardiovascular disease PCI Percutaneous coronary intervention
AV Atrioventricular PUFA Polyunsaturated fatty acid
BNP Brain natriuretic peptide REMS Risk Evaluation and Mitigation Strategy
BP Blood pressure SA Sinoatrial
BUN Blood urea nitrogen SBP Systolic blood pressure
CCB Calcium channel blocker SCr Serum creatinine
CHD Coronary heart disease SGLT2 Sodium-glucose cotransporter 2
CK Creatine kinase SR Sinus rhythm
CKD Chronic kidney disease SVR Systemic vascular resistance
CO Cardiac output TC Total cholesterol
CV Cardiovascular TEE Transesophageal echocardiogram
CYP Cytochrome P450 TG Triglycerides
DAPT Dual antiplatelet therapy TIA Transient ischemic attack
DASH Dietary Approaches to Stop Hypertension
DBP Diastolic blood pressure Self-Assessment Questions
DHA Docosahexaenoic acid Answers and explanations to these questions can be
DHP Dihydropyridine
found at the end of this chapter.
DM Diabetes mellitus
DOAC Direct oral anticoagulant
1.  .S., a 58-year-old woman with a history of hyper-
R
ECG Electrocardiogram
tension (HTN), coronary heart disease (CHD),
EPA Eicosapentaenoic acid
myocardial infarction (MI) 4 months ago, and dys-
GERD Gastroesophageal reflux disease
lipidemia, presents to the clinic for a follow-up.
GI Gastrointestinal
She has no worsening signs or symptoms of

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dyspnea or edema compared with her baseline. An C. Add spironolactone 25 mg/day.

echocardiogram reveals a left ventricular ejection D. Add empagliflozin 10 mg/day.
fraction (LVEF) of 35%. She is in New York Heart
Association (NYHA) class III. Her medications 4. B.W. is a 78-year-old man with a history of HTN,
include aspirin 81 mg/day, metoprolol succinate peripheral arterial disease (PAD), gastroesopha-
150 mg/day, and atorvastatin 40 mg/day at night. geal reflux disease, and asymptomatic atrial fibril-
Her vital signs include blood pressure (BP) 138/80 lation (AF) for the past month. His therapy includes
mm Hg and heart rate (HR) 58 beats/minute. Her aspirin 325 mg/day, lansoprazole 30 mg every
lungs are clear, and laboratory results are within night, atenolol 50 mg/day, lisinopril 10 mg/day, and
normal limits. Given her history and physical atorvastatin 20 mg/day. His vital signs include BP
examination, what is the most appropriate modifi- 132/72 mm Hg and HR 68 beats/minute. Which is
cation to R.S.’s current drug therapy? the best therapy for B.W. at this time?
A. Continue current therapy. A. Add diltiazem and rivaroxaban.
B. Initiate digoxin 0.125 mg/day. B. A
 dd digoxin and increase lisinopril to 20 mg/
C. Initiate spironolactone 25 mg/day. day.
D. Initiate lisinopril 5 mg/day. C. Discontinue atorvastatin and add warfarin.
D. Add apixaban and decrease aspirin to 81 mg/day.
2. J .O. is a 64-year-old woman with NYHA class II
nonischemic dilated cardiomyopathy (LVEF of 5.  .G. is a 61-year-old man with AF, HTN, and dys-
Z
30%). She presents to the heart failure (HF) clinic lipidemia. His medications include digoxin 0.125
for a follow-up. She is euvolemic. Her medications mg/day, warfarin 5 mg/day, amlodipine 10 mg/day,
include enalapril 10 mg twice daily, furosemide and pravastatin 20 mg every night. He comes to the
40 mg twice daily, and potassium chloride 20 mEq clinic with no complaints except for palpitations
twice daily. Her vital signs include BP 130/88 mm and shortness of breath when doing yard work. His
Hg and HR 78 beats/minute. Her laboratory results vital signs include BP 138/80 mm Hg and HR 100
are within normal limits. What is the best way to beats/minute. His international normalized ratio
manage J.O.’s HF? (INR) is 2.4, and his digoxin concentration is 1.1
A. Continue current regimen. ng/mL. All other laboratory results are within nor-
B. Increase enalapril to 20 mg twice daily. mal limits. Which is the best option to help with
Z.G.’s symptoms?
C. Initiate carvedilol 3.125 mg twice daily.
A. Add metoprolol succinate 50 mg/day.
D. Initiate digoxin 0.125 mg/day.
B. Increase digoxin to 0.25 mg/day.
3. J.M. is a 65-year-old woman with a history of C. Add verapamil 240 mg/day.
HTN who presents to her primary care physician D. C
 ontinue current regimen and advise the patient
with shortness of breath and markedly decreased to avoid activities that cause signs or symptoms.
exercise tolerance. An echocardiogram reveals
an LVEF of 65%, with diastolic dysfunction. J.M. 6.  .P. is an 69-year-old African American man with
R
currently takes losartan 150 mg/day for HTN. Her a history of HTN and gout. His medications include
vital signs include BP 134/84 mm Hg and HR 68 allopurinol 300 mg/day, amlodipine 10 mg/day,
beats/minute. Her lung fields are clear to auscul- and aspirin 81 mg/day. His vital signs include BP
tation, and there is no evidence of systemic con- 145/85 mm Hg and HR 82 beats/minute. His labo-
gestion. Her laboratory results include SCr 1.1 mg/ ratory values are normal and his 10-year ASCVD
dL and K 5.1 mEq/L. Which is the best change to risk is 22.4%. Which is the best therapy for R.P.?
make to J.M.’s pharmacologic regimen today?
A. A
 dd hydrochlorothiazide 25 mg/day to achieve
A. Add metoprolol succinate 50 mg/day. a systolic blood pressure (SBP) goal of less
B. Initiate furosemide 40 mg/day. than 130 mm Hg.

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B. A
 dd lisinopril 40 mg/day and titrate to achieve 9. J .C. is a 62-year-old man (height 70 inches, weight
an SBP goal of less than 140. 135 kg [1 month ago 143 kg]) with a history of
C. A
 dd atenolol 50 mg/day to achieve an SBP less diabetes mellitus (DM), chronic kidney disease
than 130 mm Hg. (CKD), bipolar disorder, CHD, and hypertri-
glyceridemia that, in the past, has resulted in pan-
D. M
 ake no changes to his current medications
creatitis. His family history is significant for his
because his SBP is at goal.
father having CHD and hypertriglyceridemia. He
is not a smoker, but admits drinking a 6-pack of
7. J .T. is a 58-year-old man who presents to his pri-
beer daily. Pertinent laboratory findings include a
mary care provider for the first time in 10 years.
hemoglobin A1C of 11.6% and a serum creatinine
He has smoked 2 packs/day for the past 30 years
(SCr) of 2.6 mg/dL. He currently takes atorvastatin
and takes no medication. A fasting lipid panel
40 mg every evening, aspirin 81 mg/day, metformin
shows total cholesterol (TC) 222 mg/dL, low-
1000 mg twice daily, olanzapine 10 mg/day, metop-
density lipoprotein cholesterol (LDL-C) 105 mg/dL,
rolol tartrate 50 mg twice daily, and coenzymeQ10
triglycerides (TG) 330 mg/dL, and high-density
200 mg/day. His fasting lipid profile is TC 402 mg/dL,
lipoprotein cholesterol (HDL-C) 51 mg/dL. His
LDL-C unable to calculate, HDL-C 48 mg/dL, and TG
vital signs include BP 140/75 mm Hg and HR 80
1500 mg/dL. His other laboratory values are within
beats/minute. His pooled cohort equation reveals
normal limits. Which best describes potential sec-
a 10-year atherosclerotic cardiovascular disease
ondary causes of elevated TG concentrations that
(ASCVD) risk of 14.6%. Which would be the best
should be considered in J.C.?
pharmacologic therapy to initiate in J.T.?
A. O
 besity, poorly controlled diabetes, olanzap-
A. I nitiate simvastatin 20 mg/day and gemfibrozil
ine, metoprolol, coenzyme Q10.
600 mg twice daily.
B. A
 lcohol consumption, poorly controlled dia-
B. Initiate rosuvastatin 2.5 mg/day.
betes, weight loss, metoprolol.
C. I nitiate pravastatin 20 mg/day and fenofibrate
C. O
 besity, calcium channel blockers, hyperthy-
160 mg/day.
roidism, alcohol consumption.
D. Initiate atorvastatin 20 mg/day.
D. A
 lcohol consumption, obesity, poorly con-
trolled diabetes, olanzapine, metoprolol.
8. J .S. is a 43-year-old man with HTN who presents
for an annual physical examination. His family
Questions 10 and 11 pertain to the following case.
history is significant for his father having HTN.
A.M. is a 32-year-old woman with type 1 DM and HTN.
His only medication is lisinopril 10 mg/day. His
Her current medication regimen is as follows: rami-
BP is 145/90 mm Hg. A fasting lipid profile shows
pril 10 mg/day, chlorthalidone 25 mg/day, amlodipine
TC 238 mg/dL, TG 95 mg/dL, LDL-C 176 mg/dL,
10 mg/day, ethinyl estradiol 20 mcg/norethindrone
and HDL-C 43 mg/dL. His calculated 10-year
1 mg daily (for the past 2 years), and insulin as directed.
ASCVD risk according to the pooled cohort equa-
Her vital signs today include BP 145/83 mm Hg,
tion is 3.9%. Which best describes the next step for
repeated BP 145/81 mm Hg; HR 82 beats/minute; height
management in J.S.?
66 inches; weight 70 kg. A.M. would prefer not to take
A. Initiate high-intensity statin therapy. any more drugs, if possible.
B. Initiate fenofibrate 130 mg/day.
C. Initiate moderate-intensity statin therapy. 10. Which option is the best clinical plan for A.M.?
D. D
 o not initiate statin therapy and reevaluate A. No change in therapy is currently warranted.
risk in 4–6 years. B. A
 dvise weight loss and recheck her BP in
3 months.
C. Change chlorthalidone to hydrochlorothiazide.
D. Discuss changing her contraceptive method.

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 Chronic Care in Cardiology

11. A
 .M. and her husband have decided they are ready
to have children. What is the best medication
option for A.M.?
A. No change in therapy is warranted.
B. Discontinue ramipril and replace with labetalol.
C. Increase chlorthalidone to 50 mg/day.
D. Discontinue all antihypertensive therapy.

12. A
 66-year-old African American man (height 70
inches, weight 91 kg) with AF and CHD (non–
ST-segment elevation MI and stent placement 3
years ago) presents with palpitations. Rate control
therapy, including trials of β-blockers and non-
dihydropyridine calcium channel blockers, has
been unsuccessful in controlling his symptoms. He
currently takes metoprolol succinate 50 mg/day,
aspirin 81 mg/day, atorvastatin 80 mg/day, lisino-
pril 5 mg/day, and warfarin 4 mg/day. His labora-
tory results show INR 2.2, potassium 4.8 mEq/L,
SCr 1.2 mg/dL. His BP is 110/70 mm Hg, and his
HR is 95 beats/minute. Which is the best antiar-
rhythmic therapy for him?
A. Disopyramide.
B. Flecainide.
C. Propafenone.
D. Sotalol.

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 Chronic Care in Cardiology

BPS Pharmacotherapy Specialty Examination Content Outline

This chapter covers the following sections of the Pharmacotherapy Specialty Examination Content Outline:
1. Patient-Centered Pharmacotherapy
a. 1.1. Develop patient-centered, evidence-based pharmacotherapy plans. Sub-task(s): 1.1.1 – 1.1.3, 1.1.6 –
1.1.11, 1.1.14 – 1.1.17
b. 1.2. Monitor the patient to ensure safe and effective pharmacotherapy. Sub-task(s): 1.2.1, 1.2.2
c. 1.3. Modify pharmacotherapy plans through ongoing patient assessment. Sub-task(s): 1.3.1 – 1.3.7
2. Application of Evidence to Practice and Education
a. 2.2. Evaluate pharmacotherapy-related literature and health information. Sub-task(s): 2.2.1, 2.2.3, 2.2.6

Systems and Patient Case Problems

In addition, this chapter covers the following systems and patient care problems:
1. Arrhythmias
2. Coronary artery disease
3. Dyslipidemia
4. Heart failure
5. Hypertension
6. Thromboembolic disorders

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I. HEART FAILURE

Patient Cases
1. L.S. is a 48-year-old woman with alcohol-induced cardiomyopathy. Her most recent LVEF is 20%; her daily
activities are limited by dyspnea and fatigue (NYHA class III). Her medications include lisinopril 40 mg
daily, furosemide 40 mg twice daily, carvedilol 12.5 mg twice daily, spironolactone 25 mg/day, and digoxin
0.125 mg/day. She has been stable on these doses for the past month. Her most recent laboratory results
include sodium (Na) 140 mEq/L, potassium (K) 4.0 mEq/L, chloride 105 mEq/L, bicarbonate 26 mEq/L,
blood urea nitrogen 12 mg/dL, SCr 0.8 mg/dL, glucose 98 mg/dL, calcium 9.0 mg/dL, phosphorus 2.8 mg/
dL, magnesium 2.0 mEq/L, and digoxin 0.7 ng/mL. She weighs 69 kg, and her vital signs include BP 112/70
mm Hg and HR 72 beats/minute. In the clinic today, she has concerns for increased shortness of breath and
fatigue. On physical examination, you note 2+ bilateral lower extremity pitting edema and hear crackles on
inspiration. What is the best approach for maximizing the management of her HF?
A. Increase carvedilol to 25 mg twice daily.
B. Increase lisinopril to 80 mg/day.
C. Add empagliflozin 10 mg/day.
D. Increase digoxin to 0.25 mg/day.

2. J .T. is a 62-year-old man (height 72 inches, weight 85 kg) with a history of CHD (MI 3 years ago), HTN,
depression, CKD (baseline SCr 2.8 mg/dL), PAD, osteoarthritis, hypothyroidism, and HF (LVEF of 25%).
His medications include aspirin 81 mg/day, simvastatin 40 mg every night, enalapril 5 mg twice daily, metop-
rolol succinate 50 mg/day, furosemide 80 mg twice daily, cilostazol 100 mg twice daily, acetaminophen 650
mg four times daily, sertraline 100 mg/day, and levothyroxine 0.1 mg/day. His vital signs include BP 128/74
mm Hg and HR 72 beats/minute. Pertinent laboratory results include K 4.1 mEq/L, SCr 2.8 mg/dL, and a
thyroid-stimulating hormone of 2.6 mIU/L. His HF is stable and considered NYHA class II. What is the best
approach for maximizing the management of his HF?
A. Discontinue metoprolol and begin carvedilol 12.5 mg twice daily.
B. Change enalapril to sacubitril/valsartan 24/26 mg orally twice daily.
C. Add spironolactone 25 mg/day.
D. Add digoxin 0.125 mg/day.

A. B
 ackground: HF is a complex clinical syndrome caused by any structural or functional cardiac disorder that
impairs the ability of the ventricle to fill with or eject blood.
1. Prevalence
a. Affects 6.2 million Americans
b. Prevalence increases with age
2. Heart failure with reduced ejection fraction (HFrEF)
a. Defined as a clinical diagnosis of HF and an LVEF of 40% or less
b. Dilated ventricle
c. Two thirds of cases are attributable to coronary heart disease (CHD).
d. One third of cases are attributable to nonischemic cardiomyopathy.
i. HTN
ii. Thyroid disease
iii. Obesity
iv. Stress (Takotsubo)

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v.
Cardiotoxins
(a) Alcohol
(b) Cocaine
(c) Chemotherapeutic agents
(1) Anthracyclines
(2) Cyclophosphamide (high dose)
(3) Fluorouracil
(4) Trastuzumab with or without pertuzumab/hyaluronidase
(5) Mitoxantrone
vi. Myocarditis
vii. Idiopathic
viii. Tachycardia
ix. Peripartum
3. Heart failure with preserved EF (HFpEF)
a. Defined as an LVEF of 50% or greater; borderline HFpEF is LVEF 41%–49%
b. Accounts for about 50% (highly variable) of patients with HF
c. Impaired ventricular relaxation and filling
d. Normal wall motion
e. Most common cause is HTN (60%–89%).
4. Primary symptoms
a. Dyspnea
b. Fatigue
c. Edema
d. Exercise intolerance
5. Stages and functional class of HF according to the American College of Cardiology/American Heart
Association (ACC/AHA) (Table 1)

Table 1. HF Stages and Corresponding NYHA Functional Class

ACC/AHA Stage NYHA Functional Class
A At high risk of HF (uncontrolled risk None
factors) but without structural heart
disease, cardiac biomarkers of stretch or
injury, or symptoms of HF
B No signs or symptoms of HF but with I Asymptomatic HF; no limitations in physical
structural heart disease, increased filling activity caused by HF symptoms
pressures, and/or risk factors + either
increased BNP or persistently elevated
troponin
C Structural heart disease with prior or I No limitations in physical activity caused by HF
current symptoms of HF symptoms
II Slight limitation of physical activity; asymptomatic
at rest, but symptoms of HF with normal level
of activity
III Marked limitations in physical activity because of
HF symptoms; asymptomatic at rest
IV Symptoms of HF at rest or unable to carry out any
physical activity

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Table 1. HF Stages and Corresponding NYHA Functional Class (Cont’d)

ACC/AHA Stage NYHA Functional Class
D Marked HF symptoms that interfere with IV Symptoms of HF at rest
daily life and recurrent hospitalizations
despite attempts to optimize guideline-
directed medical therapy
ACC = American College of Cardiology; AHA = American Heart Association; HF = heart failure; NYHA = New York Heart Association.
Adapted from: 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American
Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022;79:1757-80.

6. Goals of therapy
a. Modify or control risk factors (e.g., HTN, obesity, DM)
b. Manage structural heart disease
c. Reduce morbidity and mortality
d. Prevent or minimize Na and water retention
e. Eliminate or minimize HF symptoms
f. Block compensatory neurohormonal activation caused by reduced cardiac output (CO)
g. Slow progression of worsening cardiac function

B. H
 FrEF
1. Pharmacologic therapy (Figure 1)
a. General approach to therapy
i. Initiation and titration of optimal medication therapy in HFrEF should prioritize angioten-
sin receptor-neprilysin inhibitor (ARNI), β-blocker, mineralocorticoid receptor antagonist
(MRA), and sodium-glucose cotransporter 2 (SGLT2) inhibitor use to reduce CV mortality
and HF hospitalizations (Figure 1).
ii. The order of medication initiation does not necessarily need to follow the sequence of trial
publications. Rather, an individualized approach to initiation and sequencing guided by patient
symptoms, vital signs, tolerance, renal function, electrolytes, comorbidities, functional status,
and ability to follow up is recommended.
iii. Titration and optimization can occur as frequently as every 1–2 weeks.
iv. After optimizing ARNI, β-blocker, MRA, SGLT2 inhibitor, and diuretic therapy, additional
agents can be considered on the basis of patient factors (Figure 1).
b. ACE inhibitors
i. Place in therapy:
(a) Recommended in all patients with HFrEF and current or prior symptoms when use with
an ARNI is not feasible, unless contraindicated (class I indication)
(b) Often better tolerated than ß-blockers as first-line agents in patients with signs and symp-
toms of congestion/fluid overload
ii. Benefits
(a) Decreased mortality (about 25%–50% relative risk reduction compared with placebo
depending on severity of HF)
(b) Decreased hospitalizations (about 30% relative risk reduction compared with placebo)
(c) Symptom improvement
(d) Improved clinical status
(e) Improved sense of well-being
(f) Notable trials: CONSENSUS (enalapril), SOLVD (enalapril), SAVE (captopril), AIRE
(ramipril), and TRACE (trandolapril).

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Figure 1. Algorithm for pharmacologic management of heart failure with reduced ejection fraction.
HFmrEF is defined as a left ventricular ejection fraction (LVEF) of 41%–49% with evidence of spontaneous or provokable increased LV filling
a

pressures.
b
HFimpEF is defined as HF with a previous LVEF ≤ 40% and a follow-up measurement of LVEF > 40%.
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor;
HF = heart failure; HFimpEF = HF with improved ejection fraction; HFmrEF = HF with mildly reduced EF; HFpEF = HF with preserved EF;
HFrEF = HF with reduced EF; LVEF = left ventricular EF; MRA = mineralocorticoid receptor antagonist (e.g., spironolactone, eplerenone);
NP = natriuretic peptide; NYHA = New York Heart Association; PUFA = polyunsaturated fatty acid; RAAS = renin-angiotensin-aldosterone
system; SGLT2i = sodium-glucose cotransporter 2 inhibitor.

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iii. Mechanism of action

(a) Blocks production of angiotensin II
(1) Decreases sympathetic stimulation
(2) Decreases production of aldosterone and vasopressin
(3) Decreases vasoconstriction (afterload and preload)
(b) Increases bradykinins (decreases their metabolism)
(1) Increases vasodilatory prostaglandins
(2) May attenuate myocardial remodeling
iv. Dosing and administration considerations
(a) Start low and double the dose every 1–4 weeks to target dose (Table 2).
(b) ATLAS trial comparing patients with systolic dysfunction who received low-dose lis-
inopril (2.5–5 mg/day) and patients who received high-dose lisinopril (32.5–35 mg/day)
showed no difference in all-cause mortality or CV mortality; however, the high-dose
group did have a significant 12% lower risk of death or hospitalization for any reason and
24% fewer hospitalizations for HF.
(c) Patients may notice improvement in symptoms in several weeks.
(d) Avoid use in patients who have experienced angioedema as the result of previous ACE
inhibitor use or those who are pregnant or plan to become pregnant.
(e) Use caution if SBP is less than 80 mm Hg, SCr is greater than 3 mg/dL, K is greater than
5.0 mEq/L, or the patient has bilateral renal artery stenosis.
v. Monitoring
(a) Monitor SCr and K for 1–2 weeks after initiating therapy or increasing the dose, especially
in high-risk patients (preexisting hypotension, DM, K supplements, azotemia). SCr may
rise (up to a 30% increase is acceptable) because of renal efferent artery dilation (results
in a slightly decreased glomerular filtration rate). Rarely, acute renal failure occurs, espe-
cially if the patient is intravascularly depleted. Be careful to avoid overdiuresis.
(b) Monitor BP and symptoms of hypotension (e.g., dizziness, lightheadedness).
(1) BP may be low to begin with because of low CO.
(2) BP = CO × Systemic vascular resistance (SVR).
(3) In HF, as CO increases because of decreased SVR, BP may decrease slightly or
remain the same.
(4) Symptoms of hypotension are often not present with small dose increases. Remember
to treat the patient, not the number.
(c) Ninety percent of people tolerate ACE inhibitors.
(1) A ngioedema (less than 1%): Can switch to angiotensin II receptor blockers (ARBs;
cross-reactivity is 2.5%) or hydralazine–isosorbide dinitrate
(2) Cough (20%): Can switch to ARBs (less than 1%)

Table 2. ACE Inhibitors and Recommended Dosing

Drug Starting Dosage Target Dosage
Captopril 6.25 mg three times daily 50 mg three times daily
Enalapril 2.5 mg twice daily 10 mg twice daily
Lisinopril 2.5–5 mg daily 20 mg daily
Perindopril 2 mg daily 8 mg daily
Ramipril 1.25–2.5 mg daily 10 mg daily
Trandolapril 1 mg daily 4 mg daily
Note: Fosinopril and quinapril can be used; however, they do not have the same magnitude of mortality-reducing data as listed above.
ACE = angiotensin-converting enzyme

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c. Angiotensin receptor blockers

i. Place in therapy
(a) Recommended in patients with HFrEF with current or prior symptoms who are unable to
take an ACE inhibitor or ARNI (class I indication). Have not been proven superior to ACE
inhibitors at target HF dosages.
(b) Possibly considered if patient has experienced ACE inhibitor–induced angioedema
(cross-reactivity 2.5%)
(c) Often better tolerated than ß-blockers as first-line agents in patients with signs and symp-
toms of congestion/fluid overload
ii. Benefits
(a) Decreased HF-related hospitalizations and decreased death from CV causes.
(b) Notable clinical trials: CHARM-Alternative (candesartan), VALIANT (valsartan), VAL-
HEFT (valsartan), and HEAAL (losartan).
iii. Mechanism of action
(a) Selectively block the binding of angiotensin II to the angiotensin I receptor
(b) Deters vasoconstriction and aldosterone-secreting effects
(c) Does not affect ACE or inhibit kinin catabolism
iv. Dosing and administration
(a) Start low and double the dose every 1–4 weeks to target dose (Table 3).
(b) Patients may notice improvement in symptoms in several weeks.
(d) Avoid use in patients who have angioedema because of previous ARB use or those who
are pregnant or plan to become pregnant.
(e) Use caution if SBP is less than 80 mm Hg, SCr is greater than 3 mg/dL, K is greater than
5.0 mEq/L, or the patient has bilateral renal artery stenosis.
v. Monitoring
(a) SCr and K 1–2 weeks after initiating therapy or increasing the dose, especially in high-
risk patients (preexisting hypotension, DM, K supplements, azotemia)
(1) SCr may rise (up to a 30% increase is acceptable) because of renal efferent artery
dilation (results in a slightly decreased glomerular filtration rate).
(2) Rarely, acute renal failure occurs, especially if the patient is intravascularly depleted
(be careful to avoid overdiuresis).
(b) Monitor BP and symptoms of hypotension (e.g., dizziness, lightheadedness).
(c) Other adverse reactions
(1) Angioedema (rare)
(2) Cough (less than 1%)

Table 3. ARBs and Recommended Dosing

Drug Starting Dosage Target Dosage
Candesartan 4–8 mg daily 32 mg daily
Losartan 25–50 mg daily 150 mg daily
Valsartan 20–40 mg twice daily 160 mg twice daily
ARB = angiotensin receptor blocker.

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d. Sacubitril/valsartan
i. Place in therapy
(a) According to the 2022 ACC/AHA/Heart Failure Society of America (HFSA) HF guidelines
(1) ARNIs are recommended for patients with chronic HFrEF to reduce morbidity and
mortality (class I recommendation) . ARNIs are recommended over ACE inhibitors or
ARBs, when feasible (class I recommendation), as part of a direct-to-ARNI approach.
(2) In patients with chronic symptomatic NYHA class II or III HFrEF who can tolerate
an ACE inhibitor or ARB, replacement by sacubitril/valsartan is recommended to
further reduce morbidity and mortality (class I recommendation).
ii. Benefits
(a) Decreased composite endpoint of death from CV causes or hospitalization for HF (20%
relative risk reduction compared with enalapril monotherapy)
(b) Decreased all-cause mortality (16% relative risk reduction) and CV death (20% relative
risk reduction) compared with enalapril monotherapy
(c) Decreased hospitalization for HF (21% relative risk reduction compared with enalapril
monotherapy)
(d) Notable clinical trial: PARADIGM-HF
iii. Mechanism of action
(a) Sacubitril—prodrug metabolized to an active metabolite that inhibits neprilysin, increas-
ing levels of natriuretic peptides
(b) Valsartan—ARB, selectively blocks the angiotensin I receptor and inhibits angiotensin
II–dependent aldosterone release
iv. Dosing and administration considerations
(a) Initial dose
(1) Not currently taking ACE inhibitor or ARB, switching from low dose ACE inhibitor
(e.g., total daily dose of enalapril ≤10 mg, lisinopril ≤ 10 mg, ramipril ≤5 mg, or
equivalent) or ARB (e.g., total daily dose of valsartan ≤160 mg, losartan ≤50 mg,
olmesartan ≤10 mg, or equivalent), or eGFR <30 mL/min/m2: sacubitril 24 mg/
valsartan 26 mg twice daily
(2) Switching from a standard dose ACE inhibitor (e.g., total daily dose of enalapril
>10 mg, lisinopril >10 mg, ramipril >5 mg, or equivalent) or ARB (e.g., total daily
dose of valsartan >160 mg, losartan >50 mg, olmesartan >10 mg, or equivalent): sacu-
bitril 49 mg/valsartan 51 mg twice daily
(b) Maintenance dose: Double the dose every 2–4 weeks to a target dose of sacubitril 97 mg/
valsartan 103 mg twice daily, as tolerated.
(c) If switching from an ACE inhibitor, allow a 36-hour washout period before initiating
sacubitril/valsartan.
(d) Because sacubitril is a neprilysin inhibitor, BNP will increase with use. However,
NT-proBNP levels will not change.
v. Monitoring
(a) Observe for signs and symptoms of angioedema and hypotension.
(b) Monitor renal function and K 1–2 weeks after initiating therapy or increasing the dose, espe-
cially in high-risk patients (e.g., preexisting hypotension, DM, K supplements, azotemia).
(c) Monitor fluid status because patients may require a dose reduction in diuretic therapy.

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e. β-blockers
i. Place in therapy:
(a) Recommended in all patients with HFrEF with current or prior symptoms unless contra-
indicated (class I indication)
(b) Often better tolerated than than ACE inhibitors/ARBs/angiotensin receptor-neprilysin
inhibitors (ARNIs) as first-line agents in patients without signs and symptoms of conges-
tion/fluid overload
ii. Benefits (when added to an ACE inhibitor)
(a) Decreased mortality (about 35% relative risk reduction compared with placebo)
(b) Decreased hospitalizations (about 25% relative risk reduction compared with placebo)
(c) Symptom improvement
(d) Improved clinical status
(e) Notable clinical trials: CIBIS II (bisoprolol), MERIT-HF (metoprolol succinate),
COPERNICUS (carvedilol), and COMET (metoprolol tartrate vs. carvedilol).
iii. Mechanism of action
(a) Blocks the effect of norepinephrine and other sympathetic neurotransmitters on the heart
and vascular system
(1) Decreases ventricular arrhythmias (sudden cardiac death)
(2) Decreases cardiac hypertrophy and cardiac cell death
(3) Decreases vasoconstriction and HR
(b) Carvedilol also provides α1-blockade.
(1) Further decreases SVR (afterload)
(2) Results in greater reduction in BP than metoprolol succinate
iv. Dosing and administration considerations
(a) Only bisoprolol, carvedilol, and metoprolol succinate are recommended in HFrEF.
(b) Initiate when HF symptoms are stable and patients are euvolemic.
(c) Should not be prescribed without diuretics in patients with current or recent history of
fluid retention.
(d) Start low and increase (double) the dose every 1– 2 weeks (or slower, if needed) to target
dose. Aim to achieve target dose in 8–12 weeks (Table 4).
(e) Avoid abrupt discontinuation; can precipitate clinical deterioration
(f) Might not notice improvement in symptoms for several months
(g) Should be considered even in patients with reactive airway disease or asymptomatic
bradycardia

Table 4. β-Blockers and Recommended Dosing

Agent Starting Dosage Target Dosage
Bisoprolol 1.25 mg daily 10 mg daily
Carvedilol 3.125 mg twice daily 25 mg twice dailya
Carvedilol CR 10 mg daily 80 mg daily
Metoprolol succinate 12.5–25 mg daily 200 mg daily
50 mg twice daily if weight > 85 kg.
a

CR = controlled release

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v. Monitoring
(a) BP, HR, and symptoms of hypotension or bradycardia (monitor in 1–2 weeks)
(1) Significant hypotension, bradycardia, or dizziness occurs in about 1% of patients when
the β-blocker is titrated slowly. If these symptoms appear, lower the dose by 50%.
(2) Of importance, remember that higher β-blocker doses are associated with greater
mortality reduction. Therefore, if hypotension alone is the problem, try reducing the
ACE inhibitor (or another antihypertensive) first or scheduling one agent at bedtime
and one in the morning.
(b) Increased edema or fluid retention (monitor in 1–2 weeks)
(1) One percent to 2% more common than with placebo (in euvolemic, stable patients)
(2) Responds to diuretic increase
(3) Do not increase ß-blocker dose during episodes of fluid retention after therapy initia-
tion or dose titration.
(c) Fatigue or weakness
(1) One percent to 2% more common than with placebo
(2) Usually resolves spontaneously in several weeks
(3) May require dosage decrease or discontinuation
f. Mineralocorticoid receptor antagonists (MRAs)
i. Place in therapy
(a) Recommended in patients with NYHA class II–IV with an LVEF of 35% or less to reduce
morbidity and mortality unless a contraindication exists. Patients with NYHA class II
should have a history of CV hospitalization or elevated brain natriuretic peptide (BNP)
levels (class I indication).
(b) Recommended to reduce morbidity and mortality in patients after a myocardial infarction
(MI) with an LVEF less than or equal to 40% with symptoms of HF or an LVEF less than
40% and DM (class I indication).
ii. Benefits of spironolactone in NYHA class III and IV HF (RALES trial)
(a) Decreased mortality (30% relative risk reduction compared with placebo)
(b) Decreased hospitalizations for HF (35% relative risk reduction compared with placebo)
(c) Improved symptoms
iii. Benefits of eplerenone (selective MRA) in NYHA class II HF (EMPHASIS-HF)
(a) Decreased composite endpoint of death from CV causes or hospitalization from HF
(37% relative risk reduction compared with placebo)
(b) Decreased death from CV causes (24% relative risk reduction compared with placebo)
(c) Decreased hospitalizations for HF (42% relative risk reduction compared with placebo)
(d) Decreased mortality (24% relative risk reduction compared with placebo)
iv. Benefits of eplerenone in left ventricular dysfunction after MI (EPHESUS)
(a) Decreased mortality (15% relative risk reduction compared with placebo)
(b) Decreased composite endpoint of death from CV causes or hospitalization for CV events
(13% relative reduction compared with placebo)
v. Mechanism of action
(a) Blocks effects of aldosterone in the kidneys, heart, and vasculature
(b) Decreases K and magnesium loss; decreases ventricular arrhythmias
(c) Decreases Na retention; decreases fluid retention
(d) Eliminates catecholamine potentiation; decreases BP
(e) Blocks direct fibrotic actions on the myocardium

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vi. Dosing and administration considerations

(a) SCr should be less than 2.5 mg/dL for men and less than 2.0 mg/dL in women (or esti-
mated glomerular filtration rate greater than 30 mL/minute/1.73 m2), and K should be less
than or equal to 5.0 mEq/L (Table 5).
(b) In the absence of hypokalemia (K less than 4.0 mEq/L), supplemental K is not recom-
mended when taking an MRA

Table 5. MRAs and Recommended Dosing

eGFR ≥ 50 mL/min/1.73 m2 eGFR 30-49 mL/min/1.73 m2
Initial dose Maintenance dose Initial dose Maintenance dose
25 mg
Eplerenone 25 mg daily 50 mg daily 25 mg daily
every other day
12.5 mg daily or
Spironolactone 12.5–25 mg daily 25 mg daily or BID 12.5–25 mg daily
every other day
BID = twice daily; eGFR = estimated glomerular filtration rate; MRA = mineralocorticoid receptor antagonist.

vii. Monitoring
(a) K and SCr within 2–3 days, again at 7 days after starting therapy, monthly for first 3
months, and every 3 months thereafter. If the dose of ACE inhibitor or ARB is increased,
restart monitoring.
(1) Hyperkalemia was reported in only 2% of the patients in trials; however, in practice,
it occurs in about 20% of patients.
(2) Decrease dose by 50% or discontinue if K is greater than 5.5 mEq/L.
(b) Gynecomastia
(1) Spironolactone: Reported at a rate of 10% in clinical trials
(2) Eplerenone can be considered as an alternative to spironolactone if gynecomastia is
present.
g. SGLT2 inhibitors
i. Place in therapy
(a) Recommended in symptomatic HFrEF with adequate renal function regardless of DM
status
(1) Dapagliflozin: Indicated if eGFR is 25 mL/minute/1.73 m 2 or greater
(2) Empagliflozin: Indicated if eGFR is 20 mL/minute/1.73 m2 or greater
ii. Benefits
(a) Dapagliflozin (DAPA-HF) and empagliflozin (EMPEROR-Reduced) have been shown to
reduce the risk of CV death or worsening HF.
iii. Mechanism of action
(a) Inhibit the SGLT2 cotransporter in the renal proximal tubules, reducing reabsorption of
filtered glucose and increasing urinary glucose excretion
(b) Promote diuresis, reduce arterial pressure, and may reduce cardiac hypertrophy and
fibrosis
iv. Dosing
(a) Dapagliflozin: 10 mg orally daily
(b) Empagliflozin: 10 mg orally daily
v. Monitoring
(a) Monitor SCr, signs and symptoms of volume depletion, and orthostatics. Consider reduc-
ing diuretic dose because of diuretic effects.
(b) Monitor blood glucose and A1C.

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(c) A ssess patients presenting with signs or symptoms of metabolic acidosis for ketoacidosis.
Patients may experience euglycemic diabetic ketoacidosis. Discontinue SGLT2 inhibitors
before surgery to reduce the risk.
(d) Monitor for signs and symptoms of mycotic genital infections and UTIs.
h. Hydralazine/isosorbide dinitrate
i. Place in therapy
(a) Recommended in addition to optimal medical therapy to reduce morbidity and mortality
for patients self-described as African American with NYHA class III or IV HFrEF (class
I indication)
(b) May be useful in patients with current or prior symptoms of HFrEF who are unable to
tolerate an ARNI, ACE inhibitor, or an ARB (class IIa indication)
ii. Benefits
(a) Decreased mortality (43% relative risk reduction compared with placebo in African
American patients)
(b) Reduced pulmonary congestion and improved exercise tolerance
(c) Notable clinical trials: V-HeFT and A-HeFT
iii. Mechanism of action
(a) Hydralazine
(1) Arterial vasodilator (reduces afterload)
(2) Increases effect of nitrates through antioxidant mechanisms
(b) Isosorbide dinitrate
(1) Stimulates nitric acid signaling in the endothelium
(2) Venous vasodilator (reduces preload)
iv. Dosing and administration considerations
(a) Fixed-dose BiDil (hydralazine 37.5 mg plus isosorbide dinitrate 20 mg) starting at 1 tablet
three times daily with a goal dose of 2 tablets three times daily
(b) Hydralazine 75 to 300 mg daily in 3 or 4 divided doses; isosorbide dinitrate 60–120 mg
daily in 3 or 4 divided doses
v. Monitoring
(a) Headache
(b) Hypotension
(c) Drug-induced lupus (with hydralazine)
i. Diuretics
i. Place in therapy: Indicated in patients with evidence of fluid retention (class I indication)
ii. Short-term benefit (days)
(a) Decreased jugular venous distension
(b) Decreased pulmonary congestion
(c) Decreased peripheral edema
iii. Intermediate-term benefits (weeks to months)
(a) Decreased daily symptoms
(b) Increased exercise tolerance
iv. Long-term benefits (months to years): No benefit on mortality
v. Mechanism of action: Inhibit reabsorption of Na in the ascending limb of the loop of Henle
(loops) or in the distal tubule (thiazides)
vi. Dosing and administration considerations (Table 6)
(a) Should be combined with guideline-directed medical therapy
(b) Start with a low initial dose and then double the dose and titrate according to the patient’s
weight as needed. Bioavailability differs between oral loop diuretics and must be consid-
ered when converting from one agent to another.

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(c) I f a patient has fluid overload, initiate and adjust therapy to result in 0.5-1 kg of weight loss
per day (may be more aggressive in the inpatient setting).
(d) Long-term therapy should be adjusted to maintain a euvolemic state.
(e) A loop diuretic can be combined with another diuretic class (e.g., thiazide diuretic) for
synergy, if needed.
(f) Loop diuretics are preferred because of their greater diuretic capabilities; loop diuretics
also retain efficacy with decreased renal function.
vii. Monitoring: Monitor and replace K and magnesium as needed, especially with loop diuretics
(goal with cardiovascular [CV] disease is K of 4.0 mEq/L or greater and magnesium of
2.0 mEq/L or greater to minimize the risk of arrhythmias). Monitor SCr and BUN to avoid acute
kidney injury with overdiureses. Also monitor HCO3 for metabolic alkalosis with overdiuresis.

Table 6. Diuretics and Recommended Dosinga

Oral Initial Maximal Total Duration of
Agent
Bioavailability (%) Daily Dose Daily Dose (mg) Action (hr)
Loop Diuretics (inhibit 20%–25% of sodium reabsorption)
Furosemideb 10–67 20–40 mg daily or BID 600 6–8
Bumetanide b
80–100 0.5–1 mg daily or BID 10 4–6
Torsemide 80–100 10–20 mg daily 200 12–16
Ethacrynic acid b
100 25–50 mg daily or BID 200 6–8
Thiazide Diuretics (inhibit 10%–15% of sodium reabsorption)
Hydrochlorothiazide 65–75 25 mg daily or BID 200 6–12
Metolazone 40–65 2.5 mg daily 20 12–24
Chlorthalidone 64 12.5–25 mg daily 100 24–72
Chlorothiazideb 30–50 250–500 daily or BID 1000 6–12
Equivalent doses: furosemide 40 mg = bumetanide 1 mg = torsemide 10–20 mg = ethacrynic acid 50 mg.
a

Available in oral and intravenous formulations.

b

BID = twice daily.

j. Ivabradine
i. Place in therapy
(a) Novel therapy approved by the FDA in 2015
(b) According to the 2017 ACC/AHA/Heart Failure Society of America Focused Update of
the HF guidelines, ivabradine can be beneficial to reduce HF hospitalizations for patients
with symptomatic (NYHA class II and III), stable, chronic HFrEF (LVEF of 35% or less)
who are receiving evidence-based therapies, including a β-blocker at maximum tolerated
dose, and who are in sinus rhythm (SR) with an HR of 70 beats/minute or greater at rest
(class IIa recommendation).
ii. Benefits
(a) Decreased composite endpoint of CV death or hospitalization for HF (18% relative risk
reduction compared with placebo)
(b) Decreased hospitalization for HF (26% relative risk reduction compared with placebo)
(c) Notable clinical trial: SHIFT
iii. Mechanism of action: Selectively inhibits the If current in the sinoatrial node, providing HR
reduction

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iv. Dosing and administration considerations

(a) Given the well-proven mortality benefits of β-blocker therapy, patients should be receiving
β-blockers at maximally tolerated or target doses or have a contraindication to β-blocker
therapy before assessing the resting HR for consideration of ivabradine initiation.
(b) Initial dosing: Age younger than 75: 5 mg twice daily with food; age 75 and older: 2.5 mg
twice daily with food
(c) After 2–4 weeks, adjust dose according to HR:
(1) Resting HR greater than 60 beats/minute: Increase dose by 2.5 mg twice daily until
reaching the maximum dose of 7.5 mg twice daily.
(2) Resting HR 50–60 beats/minute: Continue current dose.
(3) Resting HR less than 50 beats/minute or signs/symptoms of bradycardia: Decrease
dose by 2.5 mg twice daily or discontinue if already at 2.5 mg twice daily.
(d) Maximum dose: 7.5 mg twice daily
(e) Contraindications: ADHF, BP <90/50 mm Hg, resting HR <60 beats/min, sinoatrial block,
concomitant use with strong CYP3A4 inhibitors, severe hepatic impairment (Child-Pugh
class C)
v. Monitoring
(a) Assess HR and rhythm for bradycardia (6%–10%) and AF (5%–8%) after 2 weeks of
therapy initiation or modification and periodically thereafter
(b) Phosphenes (3%): transient rings or spots of light in the visual field
k. Digoxin
i. Place in therapy: Can be beneficial in decreasing hospitalizations in patients with HFrEF
(class IIa indication); should be added after guideline-directed medical therapy
ii. Benefits
(a) Improved symptoms
(b) Improved exercise tolerance
(c) Decreased hospitalizations (28% relative risk reduction compared with placebo)
(d) No effect on mortality
(e) Notable clinical trial: DIG
iii. Mechanism of action (in HF)
(a) Inhibits myocardial Na-K adenosine triphosphatase
(b) Decreases central sympathetic outflow by sensitizing cardiac baroreceptors
(c) Decreases renal reabsorption of Na
(d) Minimal increase in cardiac contractility
iv. Dosing and administration considerations
(a) For most patients, 0.125 mg/day is adequate to achieve the desired serum concentration.
(b) Consider dosing 0.125 mg every other day in patients older than 70 years, those with
impaired renal function, or those with low lean body mass.
(c) No indication to load patients with digoxin in the setting of HF
(d) Avoid abrupt discontinuation; can precipitate clinical deterioration
(e) Drug interactions: Digoxin concentrations are increased with concomitant:
(1) Clarithromycin, erythromycin
(2) Amiodarone (reduce digoxin dose by 30%–50% or reduce dosing frequency)
(3) Dronedarone (reduce digoxin dose by 50%)
(4) Itraconazole, posaconazole
(5) Cyclosporine, tacrolimus
(6) Verapamil

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v. Monitoring
(a) Serum concentrations should be less than 1 ng/mL; in general, concentrations of 0.5–0.9
ng/mL are suggested. Serum concentrations should be obtained as a trough or at least 6–8
hours after the last dose.
(1) Minimizes the risk of adverse effects and ventricular arrhythmias associated with
increased concentrations.
(2) Risk of toxicity increases with age and renal impairment.
(3) Risk of toxicity increases in the presence of hypokalemia, hypomagnesemia, or
hypercalcemia.
(4) Signs of toxicity generally include nausea, vomiting, vision changes.
(b) SCr should be monitored because the drug is primarily cleared renally.
l. Vericiguat
i. Place in therapy: May be considered in addition to optimized HF therapy to reduce HF hospi-
talizations and CV death in patients at high risk with worsening HFrEF
ii. Benefits: Reduced the composite of death from CV causes or first hospitalization for HF com-
pared with placebo in patients with NYHA class II–IV HF with LVEF less than 45%
iii. Mechanism of action: Soluble guanylate cyclase stimulator that enhances production of cyclic
guanosine monophosphate and enhances sensitivity to endogenous nitric oxide, resulting in
smooth muscle relaxation and vasodilation
iv. Dosing and administration considerations:
(a) Initiate at 2.5 mg orally once daily and titrate to a target of 10 mg orally once daily.
(b) Take with food.
v. Monitoring: Monitor for hypotension and syncope.
m. Polyunsaturated fatty acids (PUFAs)
i. Place in therapy: Reasonable adjunctive therapy to reduce mortality and CV hospitalizations
(class 2b recommendation). Both icosapent ethyl, a highly purified eicosapentaenoic acid
(EPA), and combined EPA/docosahexaenoic acid (DHA) are included in the guidelines.
ii. Benefits: In clinical trials, reduced the risk of death or hospital admission for CV event
iii. Mechanism of action: Reduce production of very-low-density lipoproteins. The exact mecha-
nisms resulting in CV outcome benefits remain unknown.
iv. Dosing and administration considerations
(a) Icosapent ethyl: 2 g orally twice daily
(b) EPA/DHA formulations: 1000 mg of omega-3 PUFA orally daily (850 mg of EPA and 882
mg of DHA)
(c) Take either formulation with food.
v. Monitoring
(a) Bleeding events
(b) A dose-related risk of AF has been reported.
n. Potassium binders
i. Place in therapy: May be considered to improve outcomes in patients who experience hyper-
kalemia (K 5.5 mEq/L or greater) while taking a renin-angiotensin-aldosterone inhibitor (class
2b recommendation). Patiromer and sodium zirconium cyclosilicate are the agents included in
the 2022 AHA/ACC/HFSA guidelines.
ii. Benefits
(a) In clinical trials, potassium binders resulted in lower potassium concentrations and less
hyperkalemia.
(b) Patiromer has been shown to increase the number of patients able to increase spironolac-
tone dose to 50 mg compared with placebo.
(c) Clinical benefits have not yet been established.

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iii. Mechanism of action

(a) Patiromer exchanges calcium for potassium in the GI tract, increasing potassium excretion.
(b) Sodium zirconium cyclosilicate exchanges sodium and hydrogen for potassium in the GI
tract, increasing potassium excretion.
iv. Dosing and administration considerations
(a) Patiromer
(1) Powder for reconstitution that may be mixed with water, other beverages, or soft
foods like applesauce or pudding
(2) Administer other oral medications at least 3 hours before or after patiromer.
(b) Sodium zirconium cyclosilicate
(1) Powder for reconstitution that should be mixed with at least 3 tablespoons of water
before administration
(2) Administer other oral medications at least 2 hours before or after sodium zirconium
cyclosilicate.
v. Monitoring
(a) Patiromer: Monitor for hypomagnesemia.
(b) Sodium zirconium cyclosilicate: Monitor for edema.
o. Other medication therapies
i. Anticoagulation
(a) Recommended for HF with permanent, persistent, or paroxysmal AF with an additional
risk factor for stroke (no preference on agent)
(b) Reasonable for patients with HF who have permanent, persistent, or paroxysmal AF with-
out an additional risk factor for stroke
(c) Not recommended in the absence of AF, prior stroke, or a cardioembolic source
ii. Statins: Not recommended solely on the basis of HF diagnosis
iii. A ntiarrhythmics: Given the neutral effects on mortality, the preferred antiarrhythmics in
patients with HFrEF are dofetilide (AF/atrial flutter) and amiodarone.
iv. Nondihydropyridine (DHP) calcium channel blockers (CCBs) with negative inotropic effects can
be harmful in patients with a low EF and should be avoided (class III recommendation: harm).
v. DHP CCBs: DHP CCBs have no proven benefit on morbidity or mortality in HF. Use of
amlodipine can be considered for HTN or ischemic heart disease management in HF patients
because of its neutral effects on morbidity and mortality.
p. Device therapy
i. Implantable cardioverter defibrillator recommended for primary prevention of sudden cardiac
death in the following patients with ischemic or nonischemic HFrEF:
(a) Patients with ischemic or nonischemic HFrEF (LVEF of 35% of less) and NYHA class II
or III symptoms on chronic optimal medical therapy. Life expectancy should be greater
than 1 year, and patient must be at least 40 days post-MI (class I indication).
(b) Patients with HFrEF (LVEF of 30% or less) resulting from previous MI and NYHA class I
symptoms on chronic optimal medical therapy. Life expectancy should be greater than
1 year, and patient should be at least 40 days post-MI (class I indication).
ii. Chronic resynchronization therapy recommended for those with an LVEF of 35% or less,
in SR, and a left bundle branch block with a QRS of 150 milliseconds or greater on optimal
medical therapy with NYHA class II–III symptoms or NYHA class IV with ambulation
2. Nonpharmacologic therapy
a. Prevent further cardiac injury.
i. Discontinue smoking.
ii. Reduce weight if obese.

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iii. C ontrol HTN (goal BP < 130/80 mm Hg per the 2017 ACC/AHA/Heart Failure Society of
America Focused Update of the HF guidelines)
iv. Control DM.
v. Decrease alcohol intake to 2 or fewer drinks per day for men and 1 or fewer drinks per day for
women. Eliminate alcohol intake if cardiomyopathy is alcohol induced.
vi. Limit Na intake to 1500 mg/day for stages A and B; consider less than 3 g/day for stages C and D.
vii. Treat sleep apnea.
viii. Educate patient about appropriate self-care.
b. Restricting fluid intake to 1.5–2 L/day is reasonable in stage D if serum Na is low.
c. Modest exercise program benefits
i. Possible modest effects on all-cause hospitalization and all-cause mortality, CV death or CV
hospitalization, and CV death or HF hospitalization
ii. Safe for patients with HF
d. Influenza and pneumococcal vaccines
e. Monitor and appropriately replace electrolytes (to minimize risk of arrhythmias).
f. Monitor for thyroid disease.
i. Hypothyroidism can be masked by HF symptoms.
ii. Hyperthyroidism will worsen systolic dysfunction.
g. Screen for and treat depression.

Patient Case
3. W hich drug that J.T. (from Patient Case 2) is currently taking would be best to discontinue because of his
HFrEF?
A. Acetaminophen.
B. Sertraline.
C. Cilostazol.
D. Levothyroxine.

C. HFpEF: Clinical evidence for efficacious agents for HFpEF has generally been disappointing. Therapies for
symptoms, comorbidities, and risk factors that can worsen CV disease are recommended.
1. SBP and diastolic blood pressure (DBP) should be well controlled (class 1 recommendation). HTN
impairs myocardial relaxation and promotes cardiac hypertrophy.
2. Diuretics should be used for symptom relief in volume overload.
3. SGLT2 inhibitors can be beneficial to decrease HF hospitalizations and CV mortality (class 2a
recommendation).
4. MRAs and ARNIs or ARBs may be considered to decrease HF hospitalizations, particularly among
patients with LVEF on the lower end of the spectrum (class 2b recommendations).
5. Management of AF can be useful to improve symptomatic HF (class 2a recommendation).

D. HF with Mildly Reduced EF (HFmrEF)

1. Defined as HF with an LVEF of 41%–49% and evidence of spontaneous or provokable increased LV
filling pressures (e.g., elevated natriuretic peptides, hemodynamic measurements)
2. Pharmacologic recommendations
a. In patients with current or previous symptoms, use of an ARNI, ACE inhibitor, or ARB; MRA; and
metoprolol succinate, carvedilol, or bisoprolol may be considered to reduce CV mortality and HF
hospitalizations, particularly among patients with LVEF on the lower end of the spectrum (class 2b
recommendation).

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b.  GLT2 inhibitors can be beneficial for decreasing CV mortality and HF hospitalizations (class 2a
S
recommendation).

E. H
 FimpEF: HF with improved LVEF is defined as a documented LVEF of less than 40% at baseline plus a
documented LVEF improvement of 10% or greater and a second LVEF measurement of greater than 40%.
1. HFimpEF is distinct from both HFrEF and HFpEF because of distinct biology and improved outcomes
compared with the other two causes.
2. Guideline-directed medical therapy should not be discontinued in HFimpEF; discontinuation may
cause HF recurrence.

F.  edications That Cause/Exacerbate HF: An AHA scientific statement addresses medications that can cause
M
or exacerbate HF. Drugs to avoid or use with caution in HF include:
1. Drugs that promote sodium and water retention
a. Nonsteroidal anti-inflammatory drugs (NSAIDs, including selective cyclooxygenase-2 inhibitors)
i. Promote Na and water retention
ii. Blunt diuretic response
iii. Increase morbidity and mortality
b. Corticosteroids
c. Minoxidil
d. Thiazolidinediones
2. Drugs with negative inotropic effects
a. Class I and III antiarrhythmic agents (except for amiodarone and dofetilide)
i. Also have proarrhythmic effects
ii. Amiodarone and dofetilide are safe in patients with HF.
iii. Avoid dronedarone; it is contraindicated in patients with symptomatic HF with recent decom-
pensation necessitating hospitalization or NYHA class IV HF.
b. CCBs (except for amlodipine and felodipine)
i. Also promote neurohormonal activation
ii. Amlodipine and felodipine have been proven safe in patients with HF and can be added when
additional BP reduction is needed; monitor for edema.
c. Cilostazol
d. Itraconazole
3. Other
a. Metformin: Increased risk of lactic acidosis (black box warning)
b. Saxagliptin and alogliptin: Associated with increased risk of hospitalization
c. Amphetamines (e.g., methylphenidate)
i. α- and β-agonist activity
ii. Cause tachycardia
iii. Proarrhythmic effects
d. Pregabalin
i. Inhibits calcium channels
ii. Lower-extremity edema, HF exacerbation
e. Nutritional supplements
i. Lack of evidence
ii. Lack of product regulation
iii. Potential for drug interactions and/or increased risk of bleeding

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II. ATRIAL FIBRILLATION

A. Background
1. Prevalence
a. Most common arrhythmia: 2.2 million Americans
b. Prevalence increases with age.
c. Common comorbidity in patients with valvular heart disease or HF
2. Signs and symptoms
a. Some patients have no symptoms.
b. Potential symptoms that may be present to some degree include the following:
i. Palpitations
ii. Chest pain
iii. Dyspnea
iv. Fatigue
v. Lightheadedness
c. Rare cases of thromboembolic events
d. Symptoms vary with ventricular rate, underlying LVEF, AF duration, and individual patient
perceptions.
3. Classification
a. Paroxysmal: Spontaneous self-termination within 7 days of onset
b. Persistent: Lasting more than 7 days
c. Long-standing persistent: Continuous duration of more than 12 months
d. Permanent: Present all the time, unable to return to SR using pharmacologic or nonpharmacologic
options
e. Nonvalvular: The absence of moderate-severe mitral stenosis, a mechanical or bioprosthetic heart
valve, or mitral valve repair

Patient Case
4. P.M. is a 52-year-old man (height 70 inches, weight 116 kg) with a history of HTN and a transient ischemic
attack 2 years ago. He visits his primary care doctor with the chief concern of several weeks of a “flutter-
ing” feeling in his chest on occasion. He thinks the fluttering is nothing; however, his wife insists he have it
checked. His current medications include metoprolol tartrate 50 mg twice daily and aspirin 81 mg/day. He is
adherent to this regimen and has health insurance, but he does not like to make the 3-hour trip to his primary
care provider. His laboratory data from his past visit were all within normal limits. His vital signs today include
BP 130/78 mm Hg and HR 76 beats/minute. All laboratory values are within normal limits. An electrocardiogram
(ECG) reveals an irregularly irregular rhythm, with no P waves, and a HR of 74 beats/minute. A diagnosis of AF
is made. What is the best approach for managing his AF at this time?
A. Begin digoxin 0.25 mg/day.
B. Begin diltiazem CD 240 mg/day.
C. Begin warfarin 5 mg/day and titrate to a goal INR of 2.5.
D. Begin dabigatran 150 mg twice daily.

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B. Pathophysiology
1. Cardiac conduction in a normal heart and a heart with atrial fibrillation (Figure 2)

The impulse:
His 1. Is generated by the SA node.
2. Propagates through atrial tissue.
3. Reaches the AV node.
4. Passes slowly through the AV node.
5. Travels through the bundle of His.
6. Is conducted simultaneously down
the three bundle branches.
7. Is distributed to the ventricular tissue
by small embedded Purkinje fibers.

Figure 2. Cardiac conduction and atrial fibrillation.

The impulses:
1. A re generated in atrial tissues;
± focal activation, with reentry
pathways
2. Bombard the AV node in a rapid
and chaotic fashion.
3. A re propagated by the AV node
after it repolarizes from the last
impulse.
4. See 5–7 above.

Figure 2. Cardiac conduction and atrial fibrillation. (continued)

AV = atrioventricular; SA = sinoatrial.

2. ECG findings

Figure 3. Electrocardiogram showing atrial fibrillation.

3. AF causes (Table 7).

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Table 7. Potential Causes of AF

Atrial Distension High Adrenergic Tone
Chronic hypertension Alcohol withdrawal
Mitral valve disease Thyrotoxicosis
Cardiomyopathy Sepsis
Congenital defects Binge drinking
Pulmonary hypertension Surgery
Acute pulmonary embolus Sympathomimetics such as cocaine or amphetamines
Myocardial ischemia Excessive theophylline, caffeine
Sleep apnea
Emphysema or other lung diseases

C. Pharmacologic therapy
1. Ventricular rate control
a. If patients have a rapid ventricular rate, AV nodal blockade is necessary.
b. Goal HR (resting HR less than 80 beats/minute) is reasonable in symptomatic patients (class
IIa recommendation). A more lenient rate control (resting HR less than 110 beats/minute) may
be reasonable in patients who are asymptomatic and have preserved ejection fraction (class IIb
recommendation).
c. The goal is to reduce symptoms and possibly prevent tachycardia-induced cardiomyopathy.
d. Select the best agent according to individual clinical response and concomitant disease states.
i. β-Blockers
(a) Any agent with β-blockade can be used and dosed to the goal HR.
(b) Labetalol or carvedilol if additional α1-blockade is desirable (e.g., HTN)
(c) β-Blockers may be preferred in patients with a history of MI.
(d) Select carvedilol, metoprolol succinate, or bisoprolol in patients with HFrEF
(e) Avoid in patients with Wolff-Parkinson-White syndrome
(f) Effective for controlling exercise-associated HR increases
ii. Non-DHP CCBs: Verapamil or diltiazem
(a) Avoid use if there is concomitant left ventricular systolic dysfunction.
(b) May be preferred over β-blocker in patients with asthma or severe chronic obstructive
pulmonary disease
(c) Effective for controlling exercise-associated HR increases
(d) Avoid in patients with Wolff-Parkinson-White syndrome
iii. Digoxin
(a) Often ineffective alone for controlling ventricular rate in AF, especially during exercise
or movement (because of minimal effectiveness with sympathetic stimulation)
(b) Not usually first-line therapy, especially when rapid rate control is desired (2014 AHA AF
guidelines)
(c) Can be included in regimen if patient has HFrEF
(d) May be effective if additional HR control is needed when a patient is already receiving
a β-blocker, diltiazem, or verapamil
(e) Avoid in patients with Wolff-Parkinson-White syndrome
(f) May be agent of choice if patient has uncontrolled HR and decompensated HF
iv. Amiodarone
(a) May be used for rate control in patients with HF who do not have an accessory pathway
(b) May be used for rate control in patients who are refractory to other therapies such as
β-blockers, non-DHP CCBs, and digoxin

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2. Rhythm control:
a. W hen to choose a rhythm-control approach
i. Historically, maintaining SR offered no advantage over ventricular rate control and was asso-
ciated with more hospitalizations (AFFIRM trial).
ii. However, specific patients may benefit from a rhythm-control approach:
(a) Patients with intractable and intolerable symptoms such as dyspnea, palpitations, and
exercise intolerance) despite adequate rate control
(b) Patients in whom adequate ventricular rate control cannot be achieved
iii. The recent EAST-AFNET 4 trial found rhythm control (with antiarrhythmics, cardioversion,
or ablation) superior to rate control in reducing adverse CV outcomes among patients with a
recent (less than 12 months prior) diagnosis of AF and concomitant CV conditions.
iv. The most recent AF guidelines were published before release of the EAST-AFNET 4 trial.
Currently, it is reasonable to select an initial rhythm-control approach in selected patients with
a recent (less than 12 months prior) diagnosis of AF and additional CV risk factors.

Table 8. Summary of the Pros and Cons of Rate Control vs. Rhythm Control
Pros Cons
Rate control Generally easy to achieve and maintain; Electrical and structural remodeling because
strategy out-of-hospital therapy typical of continued AF makes future attainment of
SR virtually impossible; safety not proven for
younger patients
Rhythm If patient is symptomatic with fatigue and Adverse effects of antiarrhythmic medications;
control exercise intolerance, these symptoms may cost of medications and monitoring; likelihood
strategy improve if SR is attained (especially in patients of AF recurrence; in-hospital stay may be
with HF); minimizes development of structural necessary to initiate therapy
atrial changes; acceptable for all age groups
AF = atrial fibrillation; HF = heart failure; SR = sinus rhythm.

b. Cardioversion in AF
i. If cardioversion is attempted (electric or pharmacologic), the absence of atrial thrombi must
be ensured.
ii. Without anticoagulation (thrombi caused by decreased or stagnant blood flow in the atria)
(a) AF for more than 48 hours = 15% rate of atrial thrombus.
(b) AF for more than 72 hours = 30% rate of atrial thrombus.
iii. Thrombi present plus cardioversion = 91% stroke rate.
iv. Ensure safe cardioversion by either:
(a) Transesophageal echocardiogram (TEE) to visualize the atria, or
(b) Three or more weeks of therapeutic anticoagulation
(1) INR 2.0-3.0 if warfarin is selected
(2) Direct oral anticoagulants (DOACs) may also be used
v. Continue anticoagulation for at least four weeks after cardioversion with either:
(a) Warfarin or
(b) A DOAC

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vi. Specific recommendations for anticoagulation are described in Table 9.

Table 9. Anticoagulation Strategies Surrounding Cardioversion of AFa

AF Type Anticoagulation Recommendations
Unstable AF • Synchronized cardioversion; anticoagulate immediately beforehand with
parenteral therapy
• A nticoagulate for ≥4 wk after cardioversion with warfarin or a DOAC if
AF ≥ 48 hr or if duration is unknown
Stable AF, duration ACCP (CHEST) guidelines:
<48 hrb • A nticoagulate at presentation and continue through cardioversion
– LMWH or UFH at full treatment doses
• A nticoagulate for ≥4 wk afterward, regardless of baseline risk of stroke

ACC/AHA/HRS AF guidelines:
• A nticoagulation as soon as possible before cardioversion is recommended with
a CHA 2DS2-VASc score of ≥2 (men) or ≥3 (women); anticoagulation may be con-
sidered with a score of 0-1 (men) or 1-2 (women)
– UFH, LMWH, or DOAC
• Need for anticoagulation after cardioversion should be based on the patient’s risk
of thromboembolism, according to their CHA 2DS2-VASc score
Stable AF, duration ACCP (CHEST) guidelines:
unknown or >48 hr • A nticoagulate for 3 wk before cardioversion
(no TEE) – Warfarin with INR 2.0–3.0 or a DOAC
• A nticoagulate for ≥4 wk afterward, regardless of baseline risk of stroke

ACC/AHA/HRS AF guidelines:
• A nticoagulate for ≥3 wk before cardioversion
– Warfarin with INR 2.0–3.0 2.0-3.0 or DOAC, dabigatran, rivaroxaban,
apixaban, or enoxaparin (full treatment doses)
• A nticoagulate for 4 wk after cardioversion, regardless of CHA2DS2-VASc score
Stable AF, duration ACCP (CHEST) guidelines:
unknown or >48 hr • TEE-guided therapy with abbreviated anticoagulation before cardioversion
(with TEE-guided – LMWH or UFH at full treatment doses should be initiated at the time of TEE,
cardioversion) and cardioversion should be performed within 24 hr of TEE if no thrombus is seen
• A nticoagulate for ≥4 wk after cardioversion, regardless of baseline risk of stroke

ACC/AHA/HRS AF guidelines:
• If no identifiable thrombus seen on TEE, cardioversion is reasonable, provided
anticoagulation is achieved before TEE
• If thrombus identified on TEE, 3 wk of therapeutic anticoagulation is required
before cardioversion
• A nticoagulation should be maintained after cardioversion for ≥4 wk
a
Potential risk of cardioversion with antiarrhythmic drugs should be considered before treatment initiation.
b
No randomized trials have compared different anticoagulation strategies in patients with AF < 48 hr.
ACC = American College of Cardiology; ACCP = American College of Chest Physicians; AF = atrial fibrillation; AHA = American Heart
Association; DOAC = direct oral anticoagulant; HRS = Heart Rhythm Society; INR = international normalized ratio; LMWH = low-molecular-
weight heparin; TEE = transesophageal echocardiography; UFH = unfractionated heparin.
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of
patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines and the Heart Rhythm Society. Circulation 2019;140:e125-151; Lip GY, Banerjee A, Boriani G, et al. Antithrombotic therapy for
atrial fibrillation: CHEST guideline and expert panel report. Chest 2018;151:1121-201.

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c. Oral antiarrhythmic agents to induce or maintain SR (class Ic and class III agents are recom-
mended in atrial fibrillation; choice of agent depends on patient comorbidities)
i. Class Ic antiarrhythmics: 80% - 90% efficacy
(a) Flecainide and propafenone can be considered first-line therapies for patients with-
out structural heart disease (Figure 4). Propafenone also displays some nonselective
β-blocking properties.
(b) Concomitant AV nodal blocking agent (e.g., β-blocker or non-DHP CCB) typically required
(c) Contraindicated in patients with structural heart disease (including CHD, HF, left ventric-
ular hypertrophy, and valvular heart disease)
ii. Class III antiarrhythmics
(a) Amiodarone: 85%–95% efficacy
(1) Has electrophysiologic properties of classes I–IV
(2) Oral loading dose required (e.g., 400 mg 2 or 3 times per day for 2 weeks and then
400 mg/day for 4 weeks, followed by a 200-mg/day maintenance dose). Achieving a
loading dose of 10 g is desirable. Many different regimens exist.
(3) Long half-life of about 60 days
(4) In addition, has AV nodal blocking properties, which may help to control HR if AF recurs
(5) May use in patients with HF
(6) Hepatically metabolized: Cytochrome P450 (CYP) 3A4 substrate; inhibitor of
CYP3A4, CYP1A2, CYP2C9, CYP2D6, and P-glycoprotein (P-gp)
(7) Minimal incidence of ventricular arrhythmias
(8) Drug interactions (many)
(A) Digoxin: Increased digoxin exposure. Lower digoxin dose by 50%.
(B) Warfarin: Increased warfarin exposure. Lower warfarin dose by 33%–50%.
(C) Simvastatin: Increased simvastatin exposure. Do not exceed dose of 20 mg/day.
(D) Lovastatin: Increased lovastatin exposure. Do not exceed dose of 40 mg/day.
(E) β-Blockers, non-DHP CCBs, clonidine, ivabradine: Additive bradycardia
(9) Extensive monitoring for noncardiac adverse effects
(A) Liver function tests (LFTs): Baseline and every 6 months
(B) Thyroid function tests: Baseline and every 6 months
(C) Chest radiography: Baseline and annually
(D) ECG: Periodically
(E) Pulmonary function tests (including DLCO [carbon dioxide diffusion in the
lungs]): Baseline and for unexplained cough/dyspnea, chest radiographic abnor-
malities or clinical suspicion. Discontinue if pulmonary fibrosis occurs.
(F) Ophthalmologic examination: Baseline (if visual impairment) and if patient has
symptoms of visual impairment. Discontinue if optic neuritis occurs.
(G) Skin toxicities: “Blue skin” syndrome and sunburn
(H) Neurologic toxicity: Tremor, neuropathy
(I) Nausea, vomiting
(J) Adverse effects may require increased monitoring, dose reduction, or drug
discontinuation
(b) Sotalol: 50%–60% efficacy
(1) Renal excretion. Dose adjustment and vigilant corrected QT (QTc) interval monitor-
ing necessary in renal impairment. Recommended starting dose is 80 mg twice daily
(unless creatinine clearance [CrCl] less than 60 mL/minute, then once daily).
(2) Should be initiated in the hospital (minimum of 3-day stay), where QTc interval,
serum electrolytes (e.g., K and magnesium), and renal function can be monitored

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(3) C ontraindicated in patients with HF (stable or unstable); CrCl less than 40 mL/minute;
QTc interval greater than 450 milliseconds; and second- or third-degree AV block or
sick sinus syndrome (in absence of pacemaker)
(4) Possesses nonselective β-blocking properties; may result in additive bradycardia with
β-blockers, non-DHP CCBs, clonidine, ivabradine, and digoxin
(5) Sotalol is ineffective for cardioversion but may be used for maintenance of NSR
(normal SR).
(c) Dofetilide: 50%–60% efficacy
(1) Should be initiated in the hospital (minimum of 3-day stay) so that QTc interval,
serum electrolytes (e.g., K and magnesium), and renal function can be monitored
(2) Starting dose is selected based on renal function
(A) CrCl greater than 60 mL/minute: 500 mcg twice daily
(B) CrCl 40–60 mL/minute: 250 mcg twice daily
(C) CrCl 20–39 mL/minute: 125 mcg twice daily
(D) CrCl less than 20 mL/minute: Contraindicated
(3) Modification of subsequent doses is based on QTc interval measured 2–3 hours after
initial dose: QTc > 500 milliseconds (or 550 milliseconds in ventricular conduction
abnormalities) OR QTc increased greater than 15% above baseline: reduce dose by 50%
(4) If QTc is greater than 500 milliseconds (or 550 milliseconds in ventricular conduction
abnormalities) at any point after in-hospital doses 2–5, discontinue dofetilide
(5) Hepatically metabolized by CYP3A4
(6) Renal elimination through renal cationic secretion; check QTc interval if renal func-
tion declines
(7) Contraindicated in patients with CrCl less than 20 mL/minute or QTc interval greater
than 440 milliseconds (or 500 milliseconds for patients with ventricular conduction
abnormalities)
(8) May use in patients with HF
(9) Drug interactions
(A) Avoid concomitant use of the following drugs: cimetidine, verapamil, itracon-
azole, ketoconazole, hydrochlorothiazide, prochlorperazine, megestrol, dolutegra-
vir, and trimethoprim alone or in combination with sulfamethoxazole
(B) Use CYP3A4 inhibitors, triamterene, metformin, and amiloride with caution:
increased dofetilide exposure
(d) Dronedarone: 21%–25% efficacy
(1) Amiodarone analog lacking the iodine moiety that contributes to the thyroid toxicity
of amiodarone
(2) Has electrophysiologic properties of classes I–IV
(3) Dose: 400 mg twice daily with morning and evening meal
(4) Hepatically metabolized; CYP3A4 substrate; CYP3A4, CYP2D6, and P-gp inhibitor
(5) Half-life is 13–19 hours.
(6) Small increase in SCr by 0.1 mg/dL probably a result of inhibition of creatinine’s tubular
secretion; rapid onset, will plateau after 7 days, and is reversible. Monitor SCr periodically.
(7) Acute kidney injury has also been reported, and it is usually reversible with drug
discontinuation.
(8) Contraindicated in permanent AF; NYHA class II or III HF with recent decompen-
sation necessitating hospitalization; NYHA class IV HF; second- or third-degree
AV block or sick sinus syndrome (in absence of pacemaker); severe liver impairment,
HR less than 50 beats/minute; concurrent use of strong CYP3A4 inhibitors or QTc
interval–prolonging agents; history of amiodarone-induced hepatotoxicity or pulmo-
nary toxicity; pregnancy; or QTc interval 500 milliseconds or greater

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(9) O ne trial found dronedarone less effective than amiodarone for the maintenance of
SR, but with fewer adverse effects.
(10) Drug interactions
(A) Digoxin: Increased digoxin exposure; lower digoxin dose by 50%
(B) β-Blockers, non-DHP CCBs, and clonidine: Excessive bradycardia; initiate these
drugs at lowest dose. Diltiazem and verapamil can increase dronedarone expo-
sure; therefore, monitor ECG.
(C) Statins: Increased statin exposure. Limit dose of simvastatin to 10 mg/day and
lovastatin to 20 mg/day.
(D) Dabigatran: In patients with moderate renal impairment (CrCl 30–50 mL/minute),
dronedarone increases dabigatran exposure; decrease dabigatran dose to 75 mg
twice daily.
(E) Strong CYP3A4 inhibitors and inducers: Avoid.
(F) Cyclosporine, tacrolimus, sirolimus: Increased exposure of these agents; monitor
serum concentrations closely
(11) Other safety issues
(A) Liver injury: According to postmarketing surveillance, dronedarone has been
associated with rare but severe hepatic liver injury. Hepatic enzymes should be
monitored, especially during the first 6 months of treatment.
(B) Pulmonary toxicity: In postmarketing surveillance, cases of interstitial lung dis-
ease, including pneumonitis and pulmonary fibrosis, have been reported. Patients
should report any new signs of dyspnea or nonproductive cough.

No Structural Heart Disease Structural Heart Disease

CHD HF

Dofetilideb,c
Dronedarone
Flecainideb,d Dofetilideb,c
Catheter Catheter Amiodarone
Propafenoneb,d Dronedarone
ablatione ablatione Dofetilideb,c
Sotalolb,c Sotalolb,c

Amiodarone Amiodarone

Figure 4. Options for rhythm control in patients with paroxysmal and persistent atrial fibrillation. Antiarrhythmics
are listed in alphabetical order and not order of preference
a
Depends on patient preference when performed in experienced centers.
b
Not recommended with severe left ventricular hypertrophy (wall thickness > 1.5 cm).
c
Use with caution in patients at risk of torsades de pointes ventricular tachycardia.
d
Should be combined with atrioventricular nodal blocking agents.
e
Catheter ablation is only recommended as first-line therapy for patients with paroxysmal atrial fibrillation (class IIa recommendation).
CHD = coronary heart disease; HF = heart failure.
Adapted with permission from: January CT, Wann SL, Sacco RL, et al. AHA/ACC/HRS guideline for the management of patients with atrial
fibrillation. Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
and Heart Rhythm Society. Circulation 2014;130:2071.

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3. Antithrombotic therapy
a. The average annual stroke rate is 5% per year without anticoagulation.
i. A patient’s individual risk can vary from about 1% to 20% per year depending on risk factors.
ii. This risk is independent of current cardiac status (i.e., SR or AF).
b. Risk stratification and treatment determination is based on the CHA2DS2-VASc score (Tables
10–11). Of note, the 2018 CHEST guidelines for anticoagulation in atrial fibrillation no longer rec-
ommend antiplatelet therapy alone for prevention of stroke or systemic embolism.

Table 10. Risk Stratification for Antithrombotic Therapy Using the CHA2DS2-VASc Scorea
Risk Factor Score
CHF or LVEF ≤ 40% 1
Hypertension 1
Age ≥ 75 yr 2
Diabetes 1
Stroke, TIA, thromboembolism 2
Vascular disease 1
Age 65–74 yr 1
Sex category (female) 1
For use in patients with nonvalvular atrial fibrillation. Maximum point value is 9.
a

CHF = congestive heart failure; LVEF = left ventricular ejection fraction; TIA = transient ischemic attack.

Table 11. AHA/ACC/HRS Guideline Recommendations for Antithrombotic Therapy in Patients with Nonvalvular
Atrial Fibrillation per CHA2DS2-VASc Score
CHA2DS2-VASc Score = CHA2DS2-VASc Score = CHA2DS2-VASc Score =
0 in Men or 1 in Women 1 in men or 2 in women 2 in men or 3 in women
Reasonable to omit anticoagulant May consider oral anticoagulation Oral anticoagulant therapy is
therapy indicated. DOAC over warfarin
in patients eligible for DOACsa
Exclusions include moderate to severe mitral stenosis or mechanical heart valve.
a

DOAC = direct oral anticoagulant.

Patient Case
5. H.D. is a 67-year-old man with a history of HTN and AF for 4 years. His medications include ramipril 5 mg
twice daily, sotalol 120 mg twice daily, digoxin 0.125 mg/day, and warfarin 5 mg/day. He visits his primary
care physician today after being discharged from the emergency department with increased fatigue on exer-
tion, palpitations, and lower extremity edema. His vital signs today include BP 115/70 mm Hg and HR 88
beats/minute, and all laboratory results are within normal limits; however, his lower extremity edema has
worsened. His INR is 2.8. His ECG shows AF. An echocardiogram reveals an LVEF of 35%–40%. H.D.’s
physician would like to continue a rhythm control approach. What is the best treatment option for managing
his AF?
A. Discontinue sotalol and begin metoprolol succinate 12.5 mg/day.
B. Discontinue sotalol and begin dronedarone 400 mg twice daily.
C. D
 iscontinue sotalol and begin amiodarone 400 mg twice daily, tapering to goal dose of 200 mg/day for the
next 6 weeks.
D. Continue sotalol and add metoprolol tartrate 25 mg twice daily.

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D. Nonpharmacologic therapies (procedures)

1. Electrical cardioversion (low-energy cardioversion; sedation highly desirable)
2. AV nodal ablation: Ablate AV node and chronically pace the ventricles.
3. Pulmonary vein ablation: Ablates the origin of the abnormal atrial foci, which is often near the pulmo-
nary vein–atrial tissue intersection.

III. HYPERTENSION

Definition: HTN is a persistent, nonphysiologic elevation of BP; it is defined as an SBP of 130 mm Hg or greater and/or
a DBP of 80 mm Hg or greater.

A. Background
1. Prevalence
a. Most common chronic disease in the United States
b. Affects 46% of the population
c. Prevalence increases with age
d. Major modifiable risk factor for CV disease and stroke
2. Etiology
a. Essential HTN: 90% (no identifiable cause)
i. Obesity is a contributor
ii. Evaluate Na intake
b. Secondary HTN
i. Primary aldosteronism
ii. Renal parenchymal disease
iii. Renal artery stenosis
iv. Obstructive sleep apnea
v. Cushing syndrome
vi. Thyroid or parathyroid disease
vii. Medications (e.g., cyclosporine, NSAIDs, sympathomimetics)
viii. Pheochromocytoma
3. Diagnosis
a. Periodic screening for all people older than 18 years
b. Patient should be seated quietly in chair for at least 5 minutes.
c. Use appropriate cuff size (bladder length at least 80% the circumference of the arm).
d. Take BP at least twice, separated by at least 2 minutes.
e. The average BP on two separate visits is required to diagnose HTN accurately.
f. Home blood pressure monitoring (HBPM) and ambulatory blood pressure monitoring (ABPM) are
recommended to confirm diagnosis, screen for white-coat HTN, and screen for masked HTN
i. White-coat HTN: Office blood pressure is 130/80-160/100 mm Hg after a 3-month trial of life-
style modification but with daytime ABPM or HBPM blood pressure less than 130/80 mm Hg
ii. Masked HTN: Office blood pressure is 120-129/less than 80 mm Hg after a 3-month trial of
lifestyle modification; daytime ABPM or HBPM blood pressure of 130/80 or greater
4. Benefits of treating elevated BP
a. Decreased risk of stroke (by 35-40%)
b. Decreased risk of MI (by 20-25%)
c. Decreased risk of HF (by 50%)

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5. Effects of lifestyle modifications on BP (Table 12)

Table 12. Recommended Lifestyle Modifications

Approximate
Modification Recommendation SBP Reduction
Weight reduction Maintain a normal body weight (BMI 18.5–24.9 kg/m 2) 5–20 mm Hg per
10-kg weight loss
Adopt DASH eating plan Consume a diet rich in fruits, vegetables, and low-fat dairy 8–14 mm Hg
(includes substantial K products with a reduced content of saturated and total fat
intake)
Reduce Na intake Reduce Na intake to < 1500 mg/day 2–8 mm Hg
Reducing Na intake by at least 1000 mg/day will lower BP if
desired daily Na intake goal is not achieved
Physical activity Engage in regular aerobic physical activity such as brisk 4–9 mm Hg
walking (at least 30 min/day most days of the week)
Moderation of alcohol Limit consumption to: 2–4 mm Hg
consumption Men: 2 drinks/day (24 oz of beer, 10 oz of wine, or 3 oz of
80-proof whiskey)
Women and those of lower body weight: 1 drink/day
BMI = body mass index; BP = blood pressure; DASH = Dietary Approaches to Stop Hypertension; Na = sodium; SBP = systolic blood pressure.

B. Therapeutic management
1. Patient classification and management in adults (Table 13)

Table 13. Classification of BP and Hypertension and Lifestyle Modification Recommendations

BP Classification SBP (mm Hg) DBP (mm Hg)
Normal < 120 and < 80
Elevated 120-129 and < 80
Stage 1 hypertension 130-139 or 80-89
Stage 2 hypertension ≥140 or ≥ 90
Hypertensive urgency/ >180 or >120
emergency
BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure
Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-248.

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Patient Cases
6. W.D. is a 55-year-old white female who was recently admitted to the hospital with acute myocardial infarc-
tion which was treated with a stent. She has a past medical history of HTN and GERD. She is visiting your
clinic today for management of her cardiovascular medications. Her vitals today include BP 152/86 mm Hg
and HR 82 beats/minute. Her labs are all WNL, including Na 140 mEq/L, K 4.3 mEq/L, and SCr 1.0 mg/dL.
Her current medication regimen includes clopidogrel 75 mg daily, aspirin 81 mg daily, and atorvastatin 40
mg daily. What is the most appropriate approach to manage her HTN?
A. Add carvedilol monotherapy
B. Add lisinopril and metoprolol
C. Add amlodipine and metoprolol
D. Add lisinopril monotherapy

7. T.J. is a 58-year-old African American woman presenting for routine follow-up of her chronic obstructive
pulmonary disease. She has no other medical history. Her blood pressure today (average of 2 readings) is
138/88 mm Hg. Her HR is 77 beats/minute. Her BP at her last visit was 138/88 mm Hg. Her current medica-
tions include tiotropium dry powder inhaler daily and an albuterol metered dose inhaler as needed. Her labs
include Na 140 mEq/L, K 4.0 mEq/L, Cl 102 mEq/L, bicarbonate 28 mEq/L, blood urea nitrogen 14 mg/dL,
and SCr 0.8 mg/dL. Her 10-year ASCVD risk is 12.0%. What is the best approach for managing her HTN?
A. Begin diet and lifestyle modifications only
B. Begin lifestyle modifications and add amlodipine 5 mg daily
C. Begin lifestyle modifications and add lisinopril 2.5 mg daily
D. Begin lifestyle modifications and add lisinopril 2.5 mg daily plus hydrochlorothiazide 12.5 mg daily

2. The 2017 11/AHA HTN guideline blood pressure thresholds and goals are listed in Table 14.

Table 14. BP Thresholds for Goals of Pharmacologic Therapy in Patients with HTN According to Clinical Condition
Clinical Condition BP Threshold, mm Hg BP Goal, mm Hg
Clinical CVD or 10-year ASCVD risk ≥10% ≥130/80
No clinical CVD and 10-year ASCVD risk <10% ≥140/90 <130/80 for all
Diabetes mellitusa ≥130/80
Chronic kidney disease ≥130/80
Chronic kidney disease after renal transplantation ≥130/80
Heart failure ≥130/80
Stable ischemic heart disease ≥130/80
Secondary stroke prevention ≥140/90
Secondary stroke prevention (lacunar) ≥130/80
Peripheral arterial disease ≥130/80
Older persons (≥65 years; noninstitutionalized, ambulatory, ≥130 (SBP) <130 (SBP)
community-living)
According to the 2017 ACC/AHA HTN guideline.
a

ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CVD = cardiovascular disease; SBP = systolic blood pressure.

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3. Blood pressure treatment strategies according to BP and ASCVD risk are located in Figure 5.

Figure 5. BP treatment strategies according to BP level and ASCVD risk.

*I nitiation of antihypertensive drug therapy with two first-line agents of different classes, either as separate agents or in a fixed-dose combina-
tion, is recommended in adults with stage 2 HTN and an average blood pressure of greater than 20/10 mm Hg above their blood pressure target.
ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure.
Adapted from: McConnell KJ. Blood pressure management of adult patients. In: Baker WL, Beavers C, Bolesta S, et al., eds. ACCP/ASHP 2019
Cardiology Pharmacy Preparatory Review and Recertification Course, 2019. Lenexa, KS: American College of Clinical Pharmacy, 2019:95.

4. Select an appropriate drug therapy regimen

a. Initiating therapy with a single antihypertensive drug is reasonable in adults with stage 1 HTN and
a BP goal of less than 130/80 mm Hg
b. Initiating antihypertensive drug therapy with two first-line agents of different classes is recommended
in adults with stage 2 HTN and an average BP greater than 20/10 mm Hg above their BP target
c. First-line agents include thiazide diuretics, CCBs, and ACE inhibitors or ARBs.

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d. First-line agents for patients with comorbidities is described in Figure 6.

Initial medication choice

based on disease state

Stroke Coronary
Diabetes CKD HFrEF HFpEF
or TIA disease

ACEI, ACEI, ARB,

ARB, CCB, ACEI
Thiazide, or ARNI; Diuretic,
or thiazide; or ARB in BB + ACEI
ACEI, BB; AA; ACEI, ARB,
ACEI/ARB patients with or ARB
preferred or ARB as needed or BB
albuminuria
in albuminuria diuretic

Figure 6. Selecting appropriate therapy for hypertension on the basis of disease state.
AA = aldosterone antagonist; ACEI = angiotensin-receptor converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angio-
tensin receptor–neprilysin inhibitor; BB = β-blocker; CCB = calcium channel blocker; CKD = chronic kidney disease; HFpEF = heart failure
with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; TIA = transient ischemic attack.

5. Considerations with specific antihypertensive agents

a. β-Blockers
i. Evidence is insufficient to recommend β-blockers as initial therapy in patients without specific
CV comorbidities.
ii. Caution with asthma or severe chronic obstructive pulmonary disease (especially higher
doses) because of pulmonary β-receptor blockade, especially with nonselective β-blockers or
high-dose selective β-blockers.
iii. Greater risk of developing DM than with an ACE inhibitor, ARB, and CCB; use caution in
patients at high risk of DM (e.g., family history, obesity)
iv. Can mask some signs of hypoglycemia in patients with DM
v. Can cause depression
b. Thiazides
i. Can worsen gout by increasing serum uric acid
ii. May have reduced efficacy in severely impaired renal function
iii. Greater risk of developing DM than with ACE inhibitor, ARB, and CCB; use caution in
patients at high risk of DM (e.g., family history, obesity)
iv. Can assist in the management of osteoporosis by preventing urine calcium loss
v. Monitor for hyponatremia and hypokalemia.
c. ACE inhibitors and ARBs
i. Contraindicated in pregnancy
ii. Contraindicated with bilateral renal artery stenosis
iii. Monitor K closely, especially if renal impairment exists or another K-sparing drug or K sup-
plement is used.
d. Direct renin antagonist (aliskiren)
i. Avoid concurrent use with ACE inhibitors or ARBs in patients with renal impairment (CrCl
less than 60 mL/minute).
ii. Contraindicated in pregnancy

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iii. C
 ontraindicated in patients with DM when used in combination with ACE inhibitors or ARBs
because of increased risk of renal impairment, hyperkalemia, and hypotension
iv. Avoid use in combination with cyclosporine or itraconazole.
e. Calcium channel blockers
i. Dihydropyridine CCBs
(a) Amlodipine, felodipine, nifedipine
(b) Monitor for peripheral edema, reflex tachycardia, and orthostatic hypotension
(c) Useful for isolated systolic hypertension or use in African American patients
ii. Nondihydropyridine CCBs
(a) Diltiazem, verapamil
(b) Indicated in hypertensive patients with comorbid conditions which would benefit from
HR reduction (e.g., atrial fibrillation, stable angina)
(c) Contraindicated in heart block and sick sinus syndrome
(d) Potential drug interactions due to CYP450 inhibition
6. Considerations within specific patient populations
a. Patients with CHD: Potent vasodilators (hydralazine, minoxidil, and DHP CCBs) may cause reflex
tachycardia, thereby increasing myocardial oxygen demand; can attenuate this by also using an
AV nodal blocker (β-blocker or non-DHP CCB)
b. Older adult patients (65 and older):
i. Treatment of HTN with an SBP treatment goal of less than 130 mm Hg is recommended for
noninstitutionalized ambulatory community-dwelling adults with an average SBP of 130 mm
Hg or greater
ii. For older adults with HTN and a high burden of comorbidity and limited life expectancy, clini-
cal judgment, patient preference, and a team-based approach to assess risk-benefit is reasonable
for decisions regarding intensity of blood pressure lowering and choice of antihypertensives
iii. The SPRINT trial published in late 2015 showed that targeting an SBP of less than 120 mm
Hg, compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major
CV events and death from any cause among patients at high risk of CV events but without DM.
Twenty-five percent of the study population was older than 75 years.
iv. Caution with antihypertensive agents and orthostatic hypotension
c. Black patients: β-Blockers and ACE inhibitors are generally less effective as monotherapy than in
non–black patients. In black adults with HTN but without HF or CKD, including those with dia-
betes mellitus, initial antihypertensive treatment should include a thiazide-type diuretic or CCB.
β-blockers and ACE inhibitors should still be used if comorbid conditions dictate.
d. Women
i. Oral estrogen-containing contraceptives can increase BP, and the risk can increase with the
duration of use.
ii. HTN increases the risk to mother and fetus in women who are pregnant. Preferred medications
include methyldopa, nifedipine, and labetalol. ACE inhibitors, ARBs, and aliskiren should not
be used because of the potential for fetal defects.
7. Monitoring
a. Have the patient return in 4 weeks to assess efficacy (sooner if clinically indicated).
b. If there is an inadequate response with the first agent with optimal dosing (and adherence is veri-
fied) and no compelling indication exists, initiate therapy with a drug from a different class while
continuing initial therapy.

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8. Resistant HTN
a. Confirm diagnosis
i. Office BP of 130/80 mm Hg or greater and patient taking at least three antihypertensive med-
ications at optimal doses, including a diuretic (confirmed adherence) OR
ii. Office BP of <130/80 mm Hg but patient requires at least four antihypertensive medications
b. Exclude pseudoresistance
i. Ensure accurate office BP readings
ii. Exclude white-coat HTN
iii. Ensure adherence
c. Identify and reverse contributing factors
i. Lifestyle factors
(a) Obesity
(b) High-salt, low-fiber diet
(c) Physical inactivity
(d) Excessive alcohol use
ii. Interfering medications
(a) NSAIDs
(b) Sympathomimetics
(c) Stimulants
(d) Oral contraceptives
d. Screen and treat for secondary causes of HTN (described earlier)
e. Assess for target organ damage
f. Pharmacological treatment
i. Maximize diuretic therapy
(a) Use thiazide or thiazide-like diuretics if eGFR > 25-30 mL/min/m2
(1) Chlorthalidone and indapamide have the most evidence for reducing cardiovascular
outcomes
(2) Chlorthalidone is more effective at inducing predictable natriuresis in patients with
an eGFR 30-45 mL/min/m 2
(b) Use loop diuretics if eGFR < 30 mL/min/m2
ii. Add ARA (spironolactone or eplerenone)
iii. Alter dosing times to include a nocturnal dose or divide doses of drugs with half-lives <12-15 hours
iv. Add other agents from different drug classes
v. Addition of hydralazine or minoxidil requires concomitant use of a ß-blocker and diuretic
g. Follow-up
i. Ensure attainment of target BP after six months of therapy
ii. If patient not at goal, refer to appropriate specialists

IV. DYSLIPIDEMIA

A. T
 he AHA/ACC released updated Cholesterol Guidelines in 2018 in conjunction with 10 other organizations.
Major changes in new guidelines:
1. Emphasis on personalized risk assessment and shared decision making using tools listed in (D) below
2. Re-introduction of LDL-C and non-HDL-C goals
3. Recommendations for statin and nonstatin therapies

B. Goals of Therapy
1. Reduce CV morbidity and mortality
2. Achieve LDL-C goals, when appropriate

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C. Nonpharmacologic recommendations
1. Lifestyle modification is cornerstone of initial intervention
2. Heart-healthy diet
a. Recommend healthy diets such as the Dietary Approaches to Stop Hypertension (DASH) diet or
the Mediterranean Diet
b. Emphasize consumption of fruits, vegetables, whole grains, low-fat dairy products, skinless poul-
try and fish, nuts and legumes, and nontropical vegetable oils
c. Limit sweets, sugar-sweetened beverages, and red meats
d. Lower intake of saturated fats and replace with unsaturated fats (especially polyunsaturated fats)
3. Regular exercise
4. Engage in moderate-to-vigorous intensity aerobic physical activity 3-4 times per week for an average
of 40 minutes per session
5. Smoking cessation

D. Pharmacologic recommendations
1. Therapy recommendations are divided into patient management groups:
a. Secondary ASCVD prevention
b. Severe hypercholesterolemia (LDL-C ≥190 mg/dL)
c. Diabetes mellitus (DM)
d. Primary prevention
2. Pharmacologic management of dyslipidemia is detailed in Figure 7, and general principles are described
below:
a. First, initiate statin therapy if indicated. Optimize statin therapy (high intensity or maximally tol-
erated dose) before adding nonstatin therapy
b. Second, consider nonstatin therapy if additional LDL lowering is warranted.
c. According to the 2018 ACC/AHA management of blood cholesterol guidelines, ezetimibe should
generally be the first nonstatin therapy considered, followed by the addition of a proprotein con-
vertase subtilisin/kexin type 9 serine protease (PCSK9) monoclonal antibody (mAb) in selected
patient groups (Figure 7).
d. Of note, the 2022 ACC expert consensus pathway provides alternative recommendations.
i. Either ezetimibe or PCSK9 mAbs may be considered as first-line adjunctive therapy to maxi-
mally tolerated statin therapy for patients with known ASCVD or baseline LDL of 190 mg/dL
or greater. PCSK9 mAbs may be preferred in patients who require greater than 25% additional
LDL lowering.
ii. If further LDL lowering is warranted, the addition of the other nonstatin agent (ezetimibe or
PCSK9 mAb) may be considered second.
iii. If a third nonstatin therapy is warranted, the addition of bempedoic acid or the replacement of
a PCSK9 mAb with inclisiran may be considered.
3. Special populations
a. Patients age >75 years
i. Reasonable to initiate a moderate-intensity statin or continue a moderate- or high-intensity
statin if benefits outweigh risks
ii. Reasonable to discontinue statin therapy if patients have functional decline, multimorbidity,
frailty, or reduced life expectancy limits potential benefits
b. Hypertriglyceridemia
i. Primary goal is to prevent pancreatitis
ii. Evaluate for secondary causes (Table 15)

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Table 15. Common Secondary Causes of Elevated LDL-C and TG

Cause Increase LDL-C Increase TG
Medications Amiodarone, cyclosporine, Anabolic steroids, atypical antipsychotics, β-blockers, bile acid
diuretics, glucocorticoids sequestrants, glucocorticoids, hormone therapy, protease inhibitors,
raloxifine, retinoic acid, sirolimus, tamoxifen, thiazides
Dietary influences Saturated or trans fats, Very low-fat diets, high carbohydrate intake (refined), excess alcohol,
weight gain, anorexia weight gain
Disease states and Nephrotic syndrome, biliary Poorly controlled diabetes, hypothyroidism, obesity, pregnancy,
medical conditions obstruction, hypothyroidism, nephrotic syndrome, chronic renal failure, lipodystrophies
obesity, pregnancy
LDL-C = low-density lipoprotein cholesterol; TG = triglycerides.

2. Consider ezetimibe after 3. Consider PCSK9-I after

Patient Treatment Group 1. Statin therapy
statin therapy if: statin and ezetimibe if:

Very high risk (history of several major LDL ≥ 70 mg/dL or

ASCVD eventsa or one major event + High-intensity statin LDL ≥ 70 mg/dLc
non-HDL ≥ 100 mg/dLd
several high-risk conditionsb)

ASCVD High-intensity statin [goal

Age ≤ 75 yr
LDL ↓ ≥ 50%]
Not very
high risk LDL ≥ 70 mg/dL
Moderate- or high- 2. Consider ezetimibe af
Patient Management
Age > 75 yr Group intensity statin 1. Statin therapy
statin therapy if:

Age 30–75 yr with

HeFH and LDL ≥ 100
Severe Low risk (< 5%) Lifestyle modifications onlymg/dL
hypercholester
olemia (LDL ≥ Maximally tolerated statin LDL ↓ ≤ 50% and/or
190 mg/dL and therapy LDL ≥ 100 mg/dLe,f Age 40–75 yr with
age 20–75 yr) baseline LDL ≥ 220
Calculate 10- Borderline risk If risk enhancers present,
mg/dL and LDL ≥ 130
yr ASCVD risk (5%–7.4%) consider moderate-intensity mg/dL
score using statin
Primary
the PCE and May be reasonable to initiate
prevention Age 20–39 yr statin therapy if several risk
determine factors or risk enhancersg If additional LDL
(age 40–75 yr
whether risk lowering is warrantedi
and LDL 70– Moderate-intensity statin if
estimate + risk Intermediate risk
Moderate-intensity statin but high-intensity statin
189 mg/dL) benefits > risks
enhancers
Age 40–75 yr (7.5%–19.9%) 10-yr ASCVD risk ≥ therapy is not advisable
DM favor statin High-intensity statin for (goal
20%LDL ↓ 30%–49%) or tolerated, consider
patients with several ASCVD risk
therapyh factors ezetimibe or BAS
Continue previously initiated
statin therapy
Age > 75 yr High risk (≥ 20%) High-intensity statin
Initiate statin therapy if benefits (goal LDL ↓ ≥ 50%)
outweigh risks

Figure 7. Statin and nonstatin therapy recommendations according to patient treatment group.
Key:
Key: ClassII(strong)
Class (strong)recommendation.
recommendation.
Class
Class IIa(moderate)
IIa (moderate) recommendation;
recommendation;therapy is reasonable.
therapy is reasonable.
Class
Class IIb (weak) recommendation; therapy be
IIb (weak) recommendation; therapy may mayconsidered.
be considered.
a
Major ASCVD events are acute coronary syndrome (ACS) within the past 12 mo, other history of myocardial infarction
stroke, and symptomatic peripheral artery disease.
b
High-risk conditions are age ≥ 65 yr, HeFH, history of coronary artery bypass surgery or percutaneous coronary interve
ASCVD event(s), DM, hypertension, chronic kidney disease (eGFR 15–59 mL/min/1.73 m2), current smoking, histo
and persistently elevated LDL ≥ 100 mg/dL despite maximally tolerated statin therapy and ezetimibe.
c
The 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 55 m
d
Clinical evidence supports adding a PCSK9 inhibitor after maximally tolerated statin therapy, but adding ezetimibe firs
e
The 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 70 m
clinical ASCVD without FH and a target LDL reduction ≥ 50% and LDL < 55 mg/dL for patients with clinical ASC
f
MayACCP Updates
consider in Therapeutics®
adding 2023:and
a BAS to statin Pharmacotherapy Preparatory
ezetimibe if LDL Review
reduction is <and
50%Recertification
and fastingCourse
TG ≤ 300 mg/dL, especially
inhibitor therapy. 1-107
g
DM-specific risk enhancers include DM of long duration (≥ 10 yr with type 2 DM or ≥ 20 yr with type 1 DM); microva
(albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m2, retinopathy, or neuropathy; or ankle-brachial
h
If risk decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary
 2. Consider ezetimibe af
Patient Management Group 1. Statin therapy
statin therapy if:

Chronic Care in Cardiology

Low risk (< 5%) Lifestyle modifications only

3. Consider PCSK9
2. Consider ezetimibe after
Patient Management Group 1. Statin therapy inhibitor after statin and
Calculate 10- Borderline risk Ifstatin
risktherapy
enhancers
if: present, ezetimibe if:
yr ASCVD risk (5%–7.4%) consider moderate-intensity
Low risk (< 5%)
score using Lifestyle modifications only statin
Primary
the PCE and
prevention Calculate 10- determine
Borderline risk If risk enhancers present,
(age 40–75 yr (5%–7.4%) consider moderate-intensity
If additional LDL
yr ASCVD risk
and LDL 70– score using whether risk statin lowering is warrantedi
Primary
the PCE and estimate + risk Moderate-intensity statin if
189 mg/dL)
prevention Intermediate risk but high-intensity statin
determine
enhancers benefits
If additional LDL > risks
(age 40–75 yr
whether risk (7.5%–19.9%) lowering is warrantedi
therapy is not advisable
and LDL 70–
estimate + risk favor statin Moderate-intensity statin if (goal LDL ↓ 30%–49%)
but high-intensity statin or tolerated, consider
189 mg/dL) Intermediate risk
enhancers benefits > risks
therapy h
(7.5%–19.9%)
(goal LDL ↓ 30%–49%)
therapy is not advisable
ezetimibe or BAS
favor statin or tolerated, consider
therapyh ezetimibe or BAS

High risk (≥ 20%) HighHigh-intensity

risk (≥ 20%) statin High-intensity statin
(goal LDL ↓ ≥ 50%) (goal LDL ↓ ≥ 50%)
Figure 7. Statin and nonstatin therapy recommendations according to patient treatment group.
Figure
Figure
Key: 7.7.Statin
Class Statinand
I (strong) and nonstatin
nonstatin
recommendation. therapy
therapy recommendations
recommendations accordingaccording
to patient totreatment
patient treatment group.
group (Cont’d).
Key: Class
Class IIa I (strong)
(moderate) recommendation.
Key: Class I (strong) recommendation.
recommendation; therapy is reasonable.
Class IIb (weak)
Class IIa recommendation;
(moderate) therapy may be considered.
recommendation; therapy is reasonable.
a
Major ASCVDClass IIaare
events (moderate)
acute coronaryrecommendation;
syndrome (ACS) within the therapy is reasonable.
past 12 mo, other history of myocardial infarction (MI), history of ischemic
Class
Class
stroke, and IIb (weak)
IIb (weak)
symptomatic recommendation;
recommendation;
peripheral artery disease. therapy
therapy be
may may considered.
be considered.
b
aHigh-risk
Major ASCVDconditions are are
events age acute
≥ 65 yr, HeFH, history
coronary of coronary
syndrome (ACS) artery bypass
within the past surgery or percutaneous
12 mo, other history coronary intervention
of myocardial outside(MI),
infarction the major
history of
Major ASCVD events are acute coronary syndrome
(eGFR 15–59(ACS) within
m2), the past 12 mo, other history offailure,
myocardial infarction
a

ASCVD
ischemic event(s),
stroke, andDM, hypertension,
symptomatic chronicartery
peripheral kidneydisease.
disease mL/min/1.73 current smoking, history of congestive heart
andstroke, and
persistently symptomatic
elevated peripheral
LDL ≥ 100 mg/dL artery
despite maximally disease.
tolerated statin therapy and ezetimibe.
cHigh-risk conditions are age ≥ 65 yr, HeFH, history of coronary artery bypass surgery or percutaneous coronary intervention outside the major
b
The
b 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 55 mg/dL.
dASCVDHigh-risk
Clinical evidence
conditions
event(s), are agechronic
DM, hypertension,
supports adding a PCSK9
≥inhibitor
65kidney
yr,after
HeFH,
disease history
(eGFR
maximally 15–59
tolerated
ofstatin
coronary
mL/min/1.73 artery
m2),
therapy, but
bypass
current
adding
surgery
smoking,
ezetimibe
orofpercutaneous
first history congestive heart coronary interve
is more cost-effective.
e
The 2022
failure, ASCVD
andACC event(s),
expert
persistently consensus DM,
elevated LDLhypertension,
pathway on nonstatin
≥ 100 chronic
therapy
mg/dL despite suggestskidney
maximally a target disease
LDL
tolerated (eGFR
reduction
statin ≥ 50%
therapy and and15–59
LDL <mL/min/1.73
ezetimibe. 70 mg/dL for patientsm2with
), current smoking, histo
fThe 2022
c andACC
clinical persistently
ASCVD without
expert consensuselevated
FH and a
pathwayLDL
target LDL ≥ 100therapy
reduction
on nonstatin mg/dL
≥ 50% despite
and LDL
suggests
< maximally
55 mg/dL
a target
for tolerated
patients
LDL reduction
with statin
LDL <therapy
clinical
≥ 50% and
ASCVD
May consider adding a BAS to statin and ezetimibe if LDL reduction is < 50% and fasting TG ≤ 300 mg/dL, especially if ineligible for PCSK9
55 mg/dL.and ezetimibe.
and FH.
dcThe 2022 ACC expert consensus pathway on nonstatin therapy suggests a target LDL reduction ≥ 50% and LDL < 55 m
Clinical evidence
inhibitor therapy.supports adding a PCSK9 inhibitor after maximally tolerated statin therapy, but adding ezetimibe first is more cost-effective.
e d Clinical evidence supports DMadding a PCSK9 10 yrinhibitor after ≥maximally ≥tolerated statin therapy, but adding ezetimibe firs
g
The DM-specific
2022 ACC risk enhancers
expert includepathway
consensus of long duration
on nonstatin (≥
therapy with type 2a DM
suggests or LDL
target 20 yr with type
reduction 150%
DM); andmicrovascular
LDL complications
< 70 mg/dL for patients with
e (albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m2, retinopathy, or neuropathy; or ankle-brachial index < 0.9.
The
hclinical 2022
ASCVD ACCwithoutexpert
FH andconsensus pathway
a target LDL reduction on
≥ 50% nonstatin
and LDL < 55therapy
mg/dL forsuggests
patients witha clinical
target LDL
ASCVD
If risk decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary artery calcium. reduction
and FH. ≥ 50% and LDL < 70 m
f
clinical ASCVD without FH and a target LDL reduction ≥ 50% and LDL < 55 mg/dL for patients with clinical ASC
iMay consider adding a BAS to statin and ezetimibe if LDL reduction is < 50% and fasting TG ≤ 300 mg/dL, especially if ineligible for PCSK9
The 2022 ACC expert consensus pathway on nonstatin therapy suggests a target of LDL reduction ≥ 50% and LDL < 70 mg/dL.
inhibitor
f therapy.
May consider adding a BAS to statin and ezetimibe if LDL reduction is < 50% and fasting TG ≤ 300 mg/dL, especially
DM-specific risk enhancers include DM of long duration (≥ 10 yr with type 2 DM or ≥ 20 yr with type 1 DM); microvascular complications
g
inhibitor
(albuminuria
therapy.
[≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m2, retinopathy, or neuropathy; or ankle-brachial index < 0.9.
g
h
DM-specific risk enhancers include DM of long duration (≥ 10 yr with type 2 DM or ≥ 20 yr with type 1 DM); microva
If risk decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary artery calcium.
2
The
(albuminuria [≥ 30 mcg/mg creatinine]), eGFR < 60 mL/min/1.73 m , retinopathy, or neuropathy; or ankle-brachial
h 2022 ACC expert consensus pathway on nonstatin therapy suggests a target of LDL reduction ≥ 50% and LDL < 70 mg/dL.
i

ASCVD
If risk= decision is uncertain (especially in patients with borderline and intermediate risk), consider measuring coronary
atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; DM = diabetes mellitus; HeFH = heterozygous familial hyper-
i
The 2022 ACC
cholesterolemia; PCE =expert consensus
pooled cohort equation;pathway on nonstatin
PCSK9 = proprotein therapy
convertase suggests
subtilisin kexin/typea9target of LDL reduction ≥ 50% and LDL < 7
serine protease.
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 ACC/AHA/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/
PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-43; Lloyd-Jones D, Morris P, Ballantyne CM, et al. 2022
ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic
cardiovascular disease risk. J Am Coll Cardiol 2022;80:1366-418.

iii. M
 oderate hypertriglyceridemia (triglycerides [TG] 175-499 mg/dL)
(a) Address and treat lifestyle factors, comorbidities, and medications which increase TGs
(b) If persistently elevated and ASCVD risk ≥7.5%, consider initiation or intensification of
statin therapy
iv. Severe hypertriglyceridemia (TG ≥ 500 mg/dL)
(a) If persistently elevated and ASCVD risk ≥7.5%, consider initiation or intensification of
statin therapy
(b) Reasonable to implement a very low-fat diet and reasonable to initiate fibrate or omega-3
fatty acid therapy to prevent acute pancreatitis, especially if fasting TG ≥ 1000 mg/dL

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v. Expected changes in TG concentrations with drug therapy (Table 16)

Table 16. Effect of Lipid-Lowering Medications on TG

Medication % Decrease in TG
Statins 7–30
Fibrates 20–50
Niacin 20–50
Ezetimibe 5–11
Omega-3 fatty acids 19–44
TG = triglycerides

E. Risk assessment tools for primary prevention

1. Risk discussions and shared decision making with patients should consider whether lifestyle and
ASCVD risk factors have been addressed, cost considerations, and a discussion of the potential bene-
fits and adverse events of drug therapy. Patients and health care professionals should work together to
establish a customized cholesterol management plan.
2. Pooled Cohort Equation (PCE) to estimate 10-year ASCVD risk
a. Measures hard ASCVD events: fatal and nonfatal MI and stroke
b. Assists with identifying higher-risk patients for statin therapy
c. Should not be used for patients with clinical ASCVD
d. Available at http://tools.acc.org/ASCVD-Risk-Estimator/
e. Components of PCE:
i. Sex
ii. Age
iii. Race
iv. TC
v. HDL-C
vi. SBP
vii. Receiving treatment for high BP
viii. DM
ix. Smoker
3. Risk-enhancing factors
a. Family history of premature ASCVD (males <55 years, females <65 years)
b. Primary hypercholesterolemia (LDL-C 160-189 mg/dL or non-HDL-C 190-219 mg/dL)
c. Metabolic syndrome
d. CKD
e. Chronic inflammatory conditions such as psoriasis, rheumatoid arthritis, HIV/AIDS
f. History of premature menopause (age <40 years)
g. History of preeclampsia
h. High-risk race/ethnicity (e.g., South Asian ancestry)
i. Elevated TG ≥175 mg/dL
j. Elevated biomarkers such as high-sensitivity C-reactive protein, lipoprotein (a), apolipoprotein B
k. Ankle-brachial index <0.9
4. Coronary artery calcium (CAC) score for additional risk-stratification
a. If risk decision is uncertain (especially borderline and intermediate risk patients), consider measur-
ing coronary artery calcium
b. Score = 0: consider no statin (unless DM, family history of premature coronary heart disease, or
cigarette smoking present)

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c. Score = 1-99: favors statin if age ≥55

d. Score ≥100 or ≥75th percentile: favors statin

F. Monitoring
1. Measure fasting lipids 4-12 weeks after therapy initiation
2. Measure fasting lipids every 3-12 months thereafter
3. Periodically re-assess risk factors for ASCVD

G. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)

1. General approach to initiating statin therapy:
a. Fasting lipid panel
i. If baseline LDL-C is higher than 190 mg/dL, evaluate for secondary causes. If primary, screen
for familial hypercholesterolemia.
b. Alanine aminotransferase (ALT)
i. Evaluate patients with unexplained ALT more than 3x upper limit of normal
c. Hemoglobin A1C
d. Creatine kinase (if indicated)
e. Evaluate for secondary causes or conditions that may affect statin safety
2. Efficacy
a. First line for high LDL-C or CHD risk
b. When selecting a statin, consider its intensity (Table 17).
c. Reduce LDL-C by 24%–60%.
d. Reduce TG by 7%–30%.
e. Raise HDL-C by 5%–15%.
f. Reduce major coronary events.
g. Reduce CHD mortality.
h. Reduce coronary procedures (percutaneous coronary intervention [PCI] or coronary artery bypass
grafting).
i. Reduce stroke.
j. Reduce total mortality.

Table 17. Relative LDL-C-Lowering Efficacy of Statins

Atorva Fluva Pitava Lova Prava Rosuva Simva
%↓ LDL
(mg) (mg) (mg) (mg) (mg) (mg) (mg)
— 20–40 1 20 10–20 — 10 30
10 80 2 40 40 — 20 38
20 — 4 80 80 5 40 41
40 — — — — 10 — 47
80 — — — — 20 — 55
— — — — — 40 — 63
Denotes low-intensity statin; lowers LDL-C by < 30%.
Denotes moderate-intensity statin; lowers LDL-C by 30% to < 50%.
Denotes high-intensity statin; lowers LDL-C by ≥ 50%.
Atorva = atorvastatin; Fluva = fluvastatin; LDL-C = low-density lipoprotein cholesterol; Lova = lovastatin; Pitava = pitavastatin; Prava =
pravastatin; Rosuva = rosuvastatin; Simva = simvastatin.
Adapted from: Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guidelines on the treatment of blood cholesterol to reduce athero-
sclerotic cardiovascular risk in adults. Circulation 2014;129(suppl 2):S1-45.

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3.  echanism of action: Inhibits enzyme responsible for converting HMG-CoA to mevalonate (rate-
M
limiting step in production of cholesterol)
4. Main adverse effects and monitoring
a. Myopathy (can check creatine kinase [CK] at baseline and then only if muscle symptoms occur;
no regular monitoring)
b. Elevated liver enzymes
i. Obtain LFTs at baseline in all patients
ii. Perform repeated LFTs only when clinically indicated.
iii. Monitor for symptoms of hepatic injury.
5. Absolute contraindications
a. Active liver disease, unexplained persistent elevations in hepatic transaminases
b. Nursing mothers
c. Certain medications (agent-specific; see drug interactions below)
d. In 2021, the FDA requested removal of the contraindication against statin use in pregnancy.
However, statins are teratogenic and should be discontinued in most patients who are pregnant or
breastfeeding.
6. Select drug interactions (see Table 18)
a. Fibrates: Increased risk of myopathy and rhabdomyolysis when coadministered with statins. Risk
is greater with gemfibrozil than with fenofibrate.
b. Niacin: Doses greater than 1 g/day increase the risk of myopathy and rhabdomyolysis when used
concomitantly with statins; risk is lower than with fibrates; statins and niacin are commonly used
together; monitor for muscle pain.
c. Canagliflozin: A case report of a myopathy attributed to a drug interaction between canagliflozin
and rosuvastatin was recently reported.
7. Differences exist between statins in regard to pharmacokinetics and renal dosing (Tables 19 and 20)

Table 18. Select Drug Interactions with Statins

Lovastatin Pravastatin Simvastatin Fluvastatin Pitavastatin Atorvastatin Rosuvastatin
Amiodarone Daily dose Daily dose
NTE 40 mg NTE 20 mg
Amlodipine Daily dose
NTE 20 mg
Azole CI CI Daily dose Daily dose
antifungals (itraconazole, (itraconazole, NTE 20 mg BID NTE 20 mg
ketoconazole, ketoconazole, (fluconazole) (itraconazole)
posaconazole, posaconazole,
and voriconazole) and
voriconazole)
Bempedoic acid Daily dose Daily dose
NTE 40 mg NTE 20 mg
Cobicistat- CI CI
containing
products
Colchicine Use with caution Use with caution Use with caution Use with caution Use with caution Use with caution Use with caution
Cyclosporine Avoid use Daily dose CI Daily dose CI Avoid use Daily dose
NTE 20 mg NTE 20 mg BID NTE 5 mg
Danazol Daily dose CI
NTE 20 mg
Diltiazem Daily dose Daily dose
Verapamil NTE 20 mg NTE 10 mg
Dronedarone Daily dose Daily dose
NTE 20 mg NTE 10 mg
BID = twice daily;
CI = contraindicated; HIV = human immunodeficiency virus; NTE = not to exceed.

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Table 18. Select Drug Interactions with Statins (Cont’d)

Lovastatin Pravastatin Simvastatin Fluvastatin Pitavastatin Atorvastatin Rosuvastatin
Erythromycin CI Daily dose CI Daily dose Daily dose
Clarithromycin NTE 40 mg NTE 1 mg NTE 20 mg
(clarithromycin) (erythromycin) (clarithromycin)
Gemfibrozil Avoid use Avoid use CI Avoid use Avoid use Avoid use Daily dose
NTE 10 mg
Grapefruit juice Avoid use Avoid use Avoid excess
(> 1 quart per quantities
day) (> 1.2 L/day)
Lomitapide Consider Daily dose
lovastatin dose NTE 20 mg
reduction (or 40 mg if
tolerated 80 mg
for ≥1 yr)
Nefazodone CI CI
Niacin Avoid doses of Avoid doses of Avoid doses of Avoid doses of Avoid doses of Avoid doses of Use with caution
niacin niacin niacin niacin niacin niacin
≥ 1 g/day ≥ 1 g/day ≥ 1 g/day ≥ 1 g/day ≥ 1 g/day ≥ 1 g/day
HIV protease CI CI Avoid use with Daily dose
inhibitors tipranavir plus NTE 10 mg
ritonavir. Daily (lopinavir/
dose NTE 20 mg ritonavir or
(saquinavir/ atazanavir/
ritonavir, ritonavir)
darunavir/
ritonavir,
fosamprenavir or
fosamprenavir/
ritonavir)
Daily dose
NTE 40 mg
(nelfinavir)
Ranolazine Consider dose Daily dose
adjustment NTE 20 mg
Rifampin Daily dose
NTE 2 mg
BID = twice daily;
CI = contraindicated; HIV = human immunodeficiency virus; NTE = not to exceed.

Table 19. Pharmacokinetic Differences Between Statins

Half-life Elimination/
Bioavailability (%) (hr) Metabolism Prodrug Solubility
Atorvastatin 14 14 3A4 No Lipophilic
Fluvastatin 24 3 2C9 No Lipophilic
Lovastatin <5 2–3 3A4 Yes Lipophilic
Pitavastatin 43-51 12 2C9 No Lipophilic
Pravastatin 17 1.8 N/A No Hydrophilic
Simvastatin <5 2 3A4 Yes Lipophilic
Rosuvastatin 20 19 2C9 No Hydrophilic
N/A = not applicable.

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Table 20. Dosing of Statin Agents in CKD

Dose Recommended by
Drug Comments
KDIGO Guidelinesa
Atorvastatin — 20 mg/day
Fluvastatin Doses > 40 mg/day not studied in severe renal impairment 80 mg/day
Lovastatin CrCl <30 mL/min: NTE 20 mg/day Not studied
Pitavastatin CrCl 15-59 mL/min: NTE 2 mg/day 2 mg/day
Pravastatin CrCl <30 mL/min: Initial dose = 10 mg/day 40 mg/day
CrCl < 30 mL/min: Initial dose = 5 mg/day 40 mg/day
Simvastatinb (ezetimibe/simvastatin
10/20 mg/day)
Rosuvastatin CrCl < 30 mL/min: NTE 10 mg/day 10 mg/day
Recommendations for Stage 3a through Stage 5 CKD (from Kidney Disease: Improving Global Outcomes Lipid Work Group. KDIGO clinical
a

practice guidelines for lipid management in chronic kidney disease. Kidney Int 2013;3:1-56).
The 80-mg dose of simvastatin should be reserved for patients who have been taking simvastatin 80 mg long term (e.g., ≥ 12 mo) and who are
b

without evidence of muscle toxicity.

CrCl = creatinine clearance; NTE = not to exceed

H. Ezetimibe
1. Efficacy
a. Lowers LDL-C by 18%–20%
b. Can raise HDL-C by 1%–5%
c. Lowers TG by 5%–10%
2. Mechanism of action: Inhibition of cholesterol absorption
3. Adverse effects and monitoring: Diarrhea, upper respiratory tract symptoms; no monitoring necessary
4. Data suggest that combination with simvastatin is superior to simvastatin alone in prevention of CV events.

I. PCSK9 Inhibitors
1. Monoclonal antibodies (mAbs)
a. Agents: Alirocumab, evolocumab
b. Efficacy: Lower LDL-C by an additional 45%–68% when combined with statin therapy; reduce
CV events when added to statin therapy (FOURIER and ODYSSEY OUTCOMES trials)
c. Mechanism of action: Monoclonal antibodies that inhibit a protein called PCSK9, increasing cho-
lesterol clearance from the liver
d. Both indicated for heterozygous familial hypercholesterolemia or clinical ASCVD; evolocumab
also indicated for homozygous familial hypercholesterolemia
e. According to the 2018 AHA/ACC management of blood cholesterol guidelines, PCSK9 mAbs are
only indicated for select patients already receiving maximally tolerated statin therapy and ezeti-
mibe with either clinical ASCVD at very high risk or severe hypercholesterolemia in the 2018 ACC/
AHA cholesterol guidelines (Figure 7). According to the 2022 ACC expert consensus pathway on
nonstatin therapy, either PCSK9 mAbs or ezetimibe may be considered as first-line adjuvants to
maximally tolerated statin therapy.
f. Adverse effects: Injection-site reactions, respiratory infections
g. Dose:
i. Evolocumab:
(a) Heterozygous familial hypercholesterolemia or clinical ASCVD: 140 mg subcutaneously
every 2 weeks or 420 mg subcutaneously once monthly
(b) Homozygous familial hypercholesterolemia: 420 mg subcutaneously once monthly

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ii. A lirocumab: Initial dose, 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every
4 weeks; if LDL-C reduction inadequate, can adjust dose to 150 mg subcutaneously every 2
weeks
iii. PCSK9 inhibitor mAbs are preferred to inclisiran because of availability of CV outcomes data.
2. Inclisiran
a. Efficacy: Reduces LDL by 51%
b. Mechanism of action: Small synthetic interfering ribonucleic acid that inhibits translation of
PCSK9 proteins, up-regulating hepatic LDL receptor density
c. Indicated as an adjunct to maximally tolerated statin therapy in adults with heterozygous familial
hypercholesterolemia or ASCVD who require additional LDL lowering
d. Adverse effects: Injection site reactions
e. Dose: 284 mg subcutaneously at months 0 and 3, then every 6 months thereafter
f. Clinical outcomes trials are ongoing. To date, the effect of inclisiran on CV morbidity and mortal-
ity is unknown.

J. Bile acid sequestrants (cholestyramine, colestipol, colesevelam)

1. Efficacy
a. Reduce LDL-C by 15%–27%.
b. Raise HDL-C by 3%–5%.
c. May increase TG concentrations.
d. Reduce major coronary events.
2. Mechanism of action: Bind to bile acids to disrupt enterohepatic recirculation of bile acids. Liver is
stimulated to convert hepatocellular cholesterol to bile acids.
3. Adverse effects: GI distress, constipation
4. Decreased absorption of many drugs including: warfarin, amiodarone, levothyroxine, ezetimibe,
digoxin, and thiazides; administer drugs 1–2 hours before or 4 hours after bile acid sequestrant
5. Contraindications: Complete biliary obstruction, raised TG concentrations (especially greater than 400
mg/dL)

K. Niacin (Table 21)

1. Efficacy
a. Lowers LDL-C by 5%–25%
b. Lowers TG by 20%–50%
c. Raises HDL-C by 15%–35%
d. Reduces major coronary events
e. Lowers lipoprotein (a)
2. Mechanism of action: Inhibits mobilization of free fatty acids from peripheral adipose tissue to the liver
and reduces synthesis of TG, very-low-density lipoproteins, and LDL-C
3. Adverse effects and monitoring: Flushing, hyperglycemia, hyperuricemia, myopathy, upper GI dis-
tress, increased hepatic transaminases; monitor LFTs at baseline, every 6–12 weeks for first year and
then yearly
4. Sustained release appears to be more hepatotoxic than extended-release or immediate-release preparations.
5. Extended-release niacin is less likely to cause flushing.
6. Contraindications: liver disease and active peptic ulcer disease. Caution in patients predisposed to gout
7. Flushing can be minimized by taking aspirin or an NSAID 30–60 minutes before niacin, taking at bed-
time with food, using slow titration, and avoiding hot beverages, spicy foods, and hot showers around
the time of administration.
8. According to the 2018 AHA/ACC cholesterol guidelines, there are no clear indications for routine nia-
cin use for reduction of LDL-C.

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Table 21. Niacin Formulations

Drug Form Brand Name Dose Range (g)
Immediate release Niacin, Niacor 1.5–6
Extended release Niaspan 1–2
Sustained release Slo-Niacin 1–2

L. Fibrates
1. Efficacy
a. Lower LDL-C by 5%–20% (with normal TG)
b. May raise LDL-C with very high TG
c. Lower TG by 20%–50%
d. Raise HDL-C by 10%–20%
2. Mechanism of action: Reduces rate of lipogenesis in the liver
3. Adverse effects and monitoring: Dyspepsia, gallstones, myopathy, increased hepatic transaminases.
Monitor LFTs every 3 months during first year and then periodically.
4. Contraindications: Severe renal or hepatic disease, pre-existing gallbladder disease
5. Indicated for the treatment of severe hypertriglyceridemia (TGs 500 mg/dL or greater), especially in
patients with TGs 100 mg/dL or greater

M. Omega-3 fatty acids

1. Contain varying ratios of EPA and DHA
a. Omega-3 acid ethyl esters: DHA and EPA
b. Icosapent ethyl: EPA only
c. Omega-3 carboxylic acid: DHA and EPA
2. Efficacy
a. Lowers TG by 26%–45%
b. Can raise LDL-C when TG concentrations are high
c. Raises HDL-C by 5%–14%
d. Icosapent ethyl reduced the composite of CV death, nonfatal MI, nonfatal stroke, coronary revas-
cularization, or unstable angina in the REDUCE-IT trial.
3. Mechanism of action: Reduction of hepatic production of very-low-density lipoproteins; possible reduc-
tion in hepatic synthesis of TG; increased hepatic β-oxidation
4. Adverse effects: Arthralgia, GI effects (e.g., burping, taste perversion, dyspepsia); at more than 3 g/day,
bleeding (because of inhibition of platelet aggregation)
5. Dose: 2–4.8 g/day as a single dose or in two divided doses

N. Bempedoic Acid
1. Efficacy
a. Lowers LDL-C by 15%–25%
b. Reduces HDL-C by 5%
2. Mechanism of action: Inhibits ATP-citrate lyase, which inhibits cholesterol synthesis in the liver
3. Adverse effects and monitoring: Gout, hyperuricemia, leukopenia, thrombocytopenia, tendon rupture.
Monitor for signs/symptoms of hyperuricemia and tendon rupture.
4. Indicated for use as an adjunct to statin therapy in heterozygous familial hypercholesterolemia or
known CV disease in patients who require additional LDL-C reduction
5. Also available as combination product with ezetimibe
6. Results of clinical outcomes trials were not yet available at the time of publication.

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Patient Cases
8. M.M. is a 63-year-old white woman who just finished 6 months of diet and exercise for dyslipidemia. She has
a history of hypertension, DM, and asthma. She smokes one pack of cigarettes and drinks three beers per day.
Her mother had HTN and suffered an MI at age 42 years. Her father had HTN and DM. Her medications are
albuterol metered dose inhaler, lisinopril, metformin, linagliptin, and calcium carbonate antacids. Her vital
signs include BP 134/84 mm Hg and HR 75 beats/minute. Her laboratory results are as follows: HDL-C 38
mg/dL, LDL-C 134 mg/dL, TG 186 mg/dL, TC 209 mg/dL, and hemoglobin A1C 8.6%. Her pooled cohort
equation estimates a 10-year ASCVD risk of 27.8%. What is the most appropriate next step for M.M.?
A. Initiate a low-intensity statin
B. Initiate a moderate-intensity statin
C. Initiate a high-intensity statin
D. Initiate a high-intensity statin plus ezetimibe

9.  ccording to the ACC/AHA blood cholesterol guidelines, which is best described as a high-intensity statin dose?
A
A. Pravastatin 20 mg/day.
B. Lovastatin 20 mg/day.
C. Atorvastatin 40 mg/day.
D. Rosuvastatin 10 mg/day.

10. Which best describes a potential secondary cause of high TG concentrations?

A. Amiodarone.
B. Biliary obstruction.
C. Sirolimus.
D. Saturated fats.

V. CHRONIC CORONARY HEART DISEASE AND CHRONIC STABLE ANGINA

CHD is a general term that does not discriminate between the various phases the individual may cycle between
for several decades. These phases include asymptomatic disease, stable angina, progressive angina, unstable
angina, non–ST-segment elevation MI, and ST-segment elevation MI.

 epending on the patient’s manifestations, some therapies may be added or modified. However, several basic
D
treatment rules apply to all individuals with CHD, regardless of the symptoms they may experience.

The following mnemonic, developed for patients with chronic stable angina, can be applied to all patients with CHD.

A = Aspirin and antianginal therapy

B = β-Blocker and BP
C = Cigarette smoking and cholesterol
D = Diet and DM
E = Education and exercise

 lthough not all patients with CHD have DM or smoke cigarettes, the mnemonic is a way to remember the
A
primary areas that should be addressed, as applicable, in all patients with CHD.

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Some important recommendations:

• Weight reduction and maintenance to a body mass index of 18.5–24.9 kg/m 2 and a waist circumference less
than 40 inches for male patients and less than 35 inches for female patients
• Physical activity for 30–60 minutes/day, 7 days/week (minimum of 5 days/week)
• BP control
• Alcohol consumption should be limited to 1 drink (120 mL [4 ounces] of wine, 360 mL [12 ounces] of beer,
or 30 mL [1 ounce] of spirits) per day for women and 1 or 2 drinks per day for men.
• No smoking and no environmental exposure to smoke
• Reduced intake of saturated fats (to less than 7% of total calories), trans fatty acids (to less than 1% of total
calories), and cholesterol (to less than 200 mg/day)
• If a patient has DM, A1C less than 7%; a goal A1C of 7%–9% is reasonable in certain patients according to age,
history of hypoglycemia, presence of microvascular or macrovascular complications, or comorbid conditions.
• A nnual influenza vaccine

Patient Case
11. A 66-year-old man with a medical history of HTN and acute coronary syndrome with a drug-eluting coronary
stent placement 14 months ago presents to the primary care clinic. Current medications include aspirin 81
mg/day, prasugrel 10 mg/day, nitroglycerin 0.4-mg sublingual tablets as needed for chest pain, metoprolol
succinate 75 mg/day, ramipril 10 mg/day, and atorvastatin 20 mg/day. He asks you how long he will need to
take prasugrel. What is the best answer?
A. Call your physician because you may be able to stop prasugrel now.
B. Y
 our prasugrel should have been discontinued 6 months after acute coronary syndrome; discontinue
it now.
C. You will need to take prasugrel indefinitely.
D. You will need to take prasugrel for at least 18 months after your MI and stent placement.

Therapeutic Management of CHD

A. Aspirin for Stable CHD

1. Indicated in all patients with CHD unless contraindicated
2. Dose: 75–162 mg/day
3. Decreases CV events by about one third
4. Clopidogrel 75 mg/day can be used if aspirin contraindicated (e.g., allergy)
B. Antiplatelet therapy for stable CHD for patients undergoing PCI
1. Aspirin is indicated in all patients.
2.  A P2Y12 is indicated in patients who undergo PCI with stenting; clopidogrel is the only P2Y12 inhibitor
recommended in the stable ischemic heart disease (SIHD) guidelines.

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Table 22. Recommendations for Dosing and Duration of Antiplatelet Therapy in SIHD
Aspirin P2Y12 Inhibitors
Clinical Subsequent Doses
Recommended
Initial (Starting Day 2) Alternative Treatment Options
Scenario Minimum Treatment
Dose and Therapy (Class IIb)b,c
Duration (Class I)a
Duration
SIHD treated Reasonable to extend clopidogrel for
325 mg 75–100 mg/day Clopidogrel for
with PCI and > 1 month for those at low risk of
before PCI indefinitely 1 month
BMS placed bleeding
Reasonable to discontinue clopidogrel
after 3 months in those at high risk
SIHD treated
325 mg 75–100 mg/day Clopidogrel for of bleeding or those who experience
with PCI and significant overt bleedingd
before PCI indefinitely 6 months
DES placed
Reasonable to extend clopidogrel for
> 6 mo for those at low risk of bleedingd
a
Class I recommendation; defined as “should be given.”
b
Class IIb recommendation; defined as “may be considered.”
Each patient should be evaluated for his or her individual ischemic/bleeding risk, preferences, cost, etc., to determine the ideal duration of dual
c

antiplatelet therapy.
d
The DAPT Score detailed in Acute Care in Cardiology I may be used to guide decisions regarding thrombotic versus bleeding risk
BMS = bare metal stent; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; PCI = percutaneous coronary intervention; SIHD = stable
ischemic heart disease.
Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients
with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:3097-137.
Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary
artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am
Coll Cardiol 2016;68:1082-115.

C. Lipid-lowering therapy (see section IV: Dyslipidemia)

1. Counsel on healthy lifestyle habits
2. Lipid panel, baseline alanine aminotransferase; consider secondary causes of dyslipidemia, evaluate for
conditions that may influence statin safety
3. High-intensity statin therapy if without contraindications, drug–drug interactions, or history of statin
intolerance (class I recommendation)

D. ACE Inhibitors
1. Greatly decrease CV events in patients with CHD (and no left ventricular dysfunction) at high risk of
subsequent CV events.
2. Should be considered in all patients who also have an LVEF of 40% or less, HTN, DM, and/or CKD
(class I recommendation)
3. Consider using in lower-risk patients with a mildly reduced or normal LVEF in whom CV risk factors
are well controlled and revascularization has been performed (class IIb recommendation).

E. A
 RBs: Recommended as an alternative to ACE inhibitors in patients who also have an LVEF of 40% or
less, HTN, DM, or CKD or who are unable to tolerate an ACE inhibitor (e.g., cough or angioedema; class
IIa recommendation)

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F. Additional therapies for chronic stable angina

1. Definition: Predictable angina symptoms with exertion
2. Goals: Reduce symptoms of ischemia, increase physical function, and improve quality of life. In gen-
eral, achieved by either decreasing myocardial oxygen demand or increasing myocardial oxygen supply
3. Specific agents
a. β-Blockers
i. Pharmacologic effects: Decreased inotropy and HR (decrease oxygen demand)
ii. Goal resting HR 55–60 beats/minute (less than 50 beats/minute if angina symptoms continue)
iii. Goal exercise HR of no more than 75% HR associated with angina symptoms
iv. Place in therapy: May be considered chronic therapy for all patients with coronary or other
vascular disease. Should be prescribed first-line for relief of angina symptoms in patients with
stable ischemic heart disease (class I). Also a class I indication for first 3 years post-MI
v. Contraindications: Severe bradycardia (HR less than 50 beats/minute), high-degree AV block
or sick sinus syndrome (in absence of a pacemaker)
b. CCBs
i. Pharmacologic effects
(a) Decrease coronary vascular resistance and increase coronary blood flow (increase oxygen
supply)
(b) Negative inotropy, to varying degrees; nifedipine much greater than amlodipine and
felodipine (decrease oxygen demand)
(c) Decrease HR (verapamil and diltiazem only; decrease oxygen demand)
ii. Place in therapy
(a) Non-DHP CCBs may be added to β-blocker therapy to achieve HR goals (caution advised;
combination can cause heart block).
(b) Instead of β-blocker therapy when unacceptable adverse effects emerge or if treating
Prinzmetal’s angina
(c) Short-acting CCBs (nifedipine) have been associated with increased CV events; should
be avoided (except in slow-release formulations)
iii. Contraindications for non-DHP CCBs: HFrEF, severe bradycardia, high-degree AV block or
sick sinus syndrome (in absence of a pacemaker)
c. Nitrates
i. Pharmacologic effects:
(a) Endothelium-dependent vasodilation, dilates epicardial arteries and collateral vessels
(increase oxygen supply)
(b) Decreased left ventricular volume because of decreased preload mediated by venodilation
(decrease oxygen demand)
ii. Place in therapy
(a) A scheduled long-acting nitrate is useful in conjunction with a β-blocker or non-DHP
CCB, or both (to blunt the reflex sympathetic tone with nitrate therapy).
(b) As-needed sublingual tablets, powder, or spray nitroglycerin is necessary to relieve effort
or rest angina.
(c) In addition, as-needed sublingual tablets, powder, or spray nitroglycerin can be used
before exercise to avoid ischemic episodes.
iii. Caution: Hypertrophic obstructive cardiomyopathy, inferior wall MI, severe aortic valve
stenosis, avanafil within 12 hours, sildenafil and vardenafil within 24 hours, tadalafil within
48 hours

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d. Ranolazine
i. Pharmacologic effects
(a) Inhibits the late phase of the inward Na channel in ischemic myocytes during repolar-
ization, leading to a reduction in intracellular Na concentrations. This reduction in Na
concentrations leads to reduced calcium influx, which decreases ventricular tension and
myocardial oxygen consumption.
(b) Increases “oxygen efficiency”
ii. Place in therapy
(a) Ideal role is unclear
(b) Use in combination with β-blockers, CCBs, and/or nitrates when initial management with
these drugs is unsuccessful.
(c) Use when BP or HR is too low to add β-blockers, CCBs, and/or nitrates
(d) Modest reduction in hemoglobin A1C
(e) Important points
(1) No significant effects on HR or BP; thus, bradycardia and hypotension are not of
concern
(2) Dose-related QT interval prolongation
(3) Metabolized by CYP3A; P-gp substrate
(A) Avoid in hepatic dysfunction.
(B) Avoid use with strong CYP3A inhibitors, including ketoconazole, itraconazole,
clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir.
(C) Avoid use with CYP3A inducers such as rifampin, rifabutin, rifapentine, pheno-
barbital, phenytoin, carbamazepine, or St. John’s wort.
(D) Limit the dose to 500 mg twice daily in patients receiving moderate CYP3A4
inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and
grapefruit juice.

Acknowledgments: ACCP gratefully acknowledges the contribution of previous authors Drs. Jo Ellen Rodgers,
Robert Page, Sheryl Chow, and Karen J. McConnell to this chapter.

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2.  railovski E, Kim RB, Juurlink D. Rosuvastatin

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ACC guideline on lifestyle management to reduce AHA/ACP/AATS/PCNA/SCAI/STS guideline for
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2022 ACC expert consensus decision pathway on 4.  evine GN, Bates ER, Blankenship JC, et al. 2011
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the role of nonstatin therapies for LDL-cholesterol ACCF/AHA/SCAI guideline for percutaneous
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2022;80:1366-418. Association Task Force on Practice Guidelines and
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CHD and Chronic Stable Angina

1.  ihn SD, Blankenship JC, Alexander KP, et al.
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2014 ACC/AHA/AATS/PCNA/SCAI/STS focused
update of the guideline for the diagnosis and man-
agement of patients with stable ischemic heart dis-
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American Heart Association Task Force on Practice
Guidelines, and the American Association for
Thoracic Surgery, Preventive Cardiovascular

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ANSWERS AND EXPLANATIONS TO PATIENT CASES

1. Answer: C Acetaminophen is the drug of choice for mild to mod-

This patient has NYHA class III HFrEF with an LVEF erate pain in patients with HF, because NSAIDs can
of 20%. The best option is to add empagliflozin 10 mg lead to water retention and worsening HF symptoms
orally daily to reduce CV mortality and HF hospital- (Answer A). The selective serotonin reuptake inhibi-
izations (Answer C is correct). Appropriate monitor- tors are not contraindicated in HF (Answer B). Properly
ing would include signs and symptoms of hypotension dosed thyroid replacement therapy, as evidenced by
and genitourinary infections. Although increasing this his therapeutic thyroid-stimulating hormone concen-
patient’s carvedilol dose (Answer A) is desirable long tration, is also beneficial because both hypothyroidism
term, the patient currently has signs and symptoms of and hyperthyroidism have negative consequences in
fluid overload; adding or increasing doses of ß-blockers patients with HF (Answer D).
is not advisable in this setting. The ACE inhibitor is
already at the maximum recommended lisinopril dose 4. Answer: D
for HF; therefore, further increases are not warranted This patient’s ventricular rate is well controlled with
(Answer B). Her digoxin concentration of 0.7 ng/dL is his metoprolol tartrate therapy; therefore, an additional
within the desired range of 0.5–0.9 ng/mL; therefore, AV nodal-blocking agent is unnecessary and would
no dose increase is warranted because this would not increase the risk of adverse events and heart block. If
improve efficacy and would only increase the risk of additional rate control is desired, the metoprolol dose
toxicity (Answer D). could first be increased, but the patient’s heart rate is
currently within the goal range (Answers A and B are
2. Answer: B incorrect). This patient with AF would be considered
An ACE inhibitor or ARB should be changed to an at high risk of a stroke because of his history of HTN
ARNI in all patients with HFrEF, if possible (Answer B and TIA. Given these risk factors, this patient has a
is correct). This patient’s blood pressure and SCr safely CHA2DS2-VASc score of 3; therefore, anticoagulation
permit this change. Because the patient was taking a with an oral anticoagulant agent is indicated. Warfarin
low dose of enalapril, the appropriate starting dose for titrated to a goal INR of 2.5 would be a potentially
sacubitril/valsartan is 24/26 mg orally twice daily. The appropriate option; however, this patient may be unable
clinician should remember to allow a 36-hour washout to travel to his primary care provider’s office for weekly
period between ACE inhibitor and ARNI doses. There INR checks, and DOACs are preferred to warfarin for
is no consensus that carvedilol is preferred to extend- DOAC-eligible patients (Answer C). In this case, dab-
ed-release metoprolol for patients with HFrEF (Answer igatran 150 mg twice daily (Answer D) may be the best
A is incorrect). Spironolactone is not appropriate to ini- choice because it does not warrant INR monitoring,
tiate in this patient because his baseline SCr concentra- the patient has prescription insurance, he appears to be
tion is greater than 2.5 mg/dL (Answer C is incorrect). adherent to a twice-daily medication regimen already,
Digoxin should be added only in patients who continue and he does not have renal impairment.
to have symptoms or hospitalizations despite optimized
therapy with an ACE inhibitor/ARB/ARNI, β-blocker, 5. Answer: C
MRA, SGLT2 inhibitor, and diuretic, and this patient’s With the new diagnosis of HFrEF, this patient can no
therapy is not considered optimal. In addition, digoxin longer receive sotalol. Discontinuing this medication
0.125 mg daily would likely be too high for a patient is important so that his risk of arrhythmic death is not
with an SCr of 2.8 mg/dL. This patient’s ACE inhib- increased. Adding metoprolol is a reasonable approach,
itor therapy is not considered optimal (Answer D is but not until his HF has been properly controlled, mak-
incorrect). ing both Answers A and D incorrect. If rhythm control
is desired, amiodarone and dofetilide are the only two
3. Answer: C antiarrhythmic drugs that have been proven safe and
Cilostazol, a phosphodiesterase type 3 inhibitor, may be effective in patients with HFrEF, making Answer C
associated with an elevated risk of ventricular arrhyth- correct. Of importance, drug interactions exist between
mias and death in patients with HFrEF (Answer C). amiodarone, digoxin, and warfarin, which will need to

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be addressed. Dronedarone (Answer B) is not recom- 9. Answer: C

mended in patients with symptomatic HF with a recent A high-intensity statin should provide a ≥50% reduction
decompensation. in LDL-C. Atorvastatin 40 mg is considered a high-
intensity statin because it will lower LDL by more than
6. Answer: B 50% (Answer C is correct). Pravastatin 20 mg (Answer
W.D.’s blood pressure falls into the stage 2 HTN cate- A) and lovastatin 20 mg (Answer B) are considered
gory. The ACC/AHA guidelines recommend two-drug low-intensity statins because they will lower LDL by
therapy for patients with stage 2 HTN, making answers less than 30%. Rosuvastatin 10 mg will reduce LDL
A and D incorrect. This patient recently suffered from 30%–50%; therefore, it is considered a moderate-
a myocardial infarction, and the ACC/AHA guidelines intensity statin (Answer D).
recommend both β-blockers and ACE inhibitors or
ARBs for treatment of HTN in ischemic heart disease, 10. Answer: C
making answer B correct and Answer C incorrect. If fasting TG concentrations are 500 mg/dL or greater
or LDL-C is greater than 190 mg/dL, patients should
7. Answer: B be assessed for potential secondary causes of their dys-
T.J.’s blood pressure falls into the stage 1 HTN cate- lipidemia. Secondary causes of elevated TG include
gory. Because the patient’s 10-year ASCVD risk is 10% high intake of carbohydrates, excessive alcohol intake,
or greater, her blood pressure treatment threshold is oral estrogens, glucocorticoids, protease inhibitors,
130/80 mm Hg or greater. Therefore, pharmacologic sirolimus (Answer C), thiazides, anabolic steroids, ral-
treatment is warranted, making Answer A incorrect. oxifene, β-blockers, nephrotic syndrome, CKD, lipo-
Because she has stage 1 HTN, she should be started dystrophies, poorly controlled DM, hypothyroidism,
on a single drug regimen, making answer D incor- pregnancy, and obesity. Amiodarone (Answer A), bili-
rect. According to the ACC/AHA guidelines, patients ary obstruction (Answer B), and saturated fats (Answer
without medical conditions that direct drug therapy D) are all secondary causes of increased LDL-C.
choices can be initiated on ACE inhibitors, ARBs, thi-
azide diuretics, or calcium channel blockers. However, 11. Answer: A
because this patient is African American and she does After placement of a drug-eluting stent for acute cor-
not have heart failure, CKD, or type 2 diabetes with onary syndrome, a P2Y12 inhibitor is indicated for 12
albuminuria, her initial HTN regimen should include a months in most patients (Answer A is correct). Answer
calcium channel blocker or a thiazide diuretic because B is incorrect because 6 months of dual antiplatelet
these agents are more effective at lowering BP than therapy (DAPT) is only for patients at high risk of
ACE inhibitors and ARBs. Therefore, answer C is bleeding, and this patient has no indication of being at
incorrect and answer B is the best choice. high risk of bleeding. No current data support DAPT
indefinitely (Answer C is incorrect). Answer D is incor-
8. Answer: C rect because the guidelines recommend DAPT for at
This patient falls into the patient management group least 12 months, not 18, in most patients.
of patients with diabetes and age 40-75 years. Because
she has multiple ASCVD risk factors including smok-
ing, low HDL-C, and HTN, this patient would benefit
from high-intensity statin therapy (answer C). Answer
B would be correct if M.M. did not have additional
ASCVD risk factors. Low-intensity statins are not rec-
ommended for initial therapy for any patient in the 2018
ACC/AHA Cholesterol guidelines (answer A). This
patient should receive maximally tolerated statin ther-
apy and be assessed for response before the addition of
ezetimibe (Answer D).

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ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS

1. Answer: D is an appropriate therapy for patients with HFpEF, espe-

This patient has HFrEF (NYHA class III), probably cially in the context of HTN, this patient’s potassium is
secondary to her MI 4 months ago, and is not receiv- greater than 5.0 mEq/L, so MRA therapy should not be
ing optimal HF therapy with an ACE inhibitor and initiated.
β-blocker, making Answer A incorrect. ACE inhibi-
tors are considered a cornerstone of therapy for HFrEF 4. Answer: D
because evidence shows that they slow the progression This patient’s CHA 2DS2-VASc score is 4 (risk factors
of HF and reduce symptoms, hospitalizations, and mor- are HTN, PAD, and age greater than 75 years), mak-
tality in this patient population. ACE inhibitors should ing him a candidate for an oral anticoagulant, such as
be initiated in all patients with HFrEF, unless there is rivaroxaban, because of his AF. Use of an oral antico-
a contraindication. This patient has no contraindica- agulant will greatly decrease his risk of stroke from
tions for using an ACE inhibitor; therefore, lisinopril about 5% per year to about 1% per year. Because his
should be initiated (Answer D). Digoxin is not indicated HR is less than 110 beats/minute with atenolol therapy,
unless a patient is symptomatic on optimal HF therapy there is no reason to discontinue atenolol. In addition,
(Answer B). This patient is not symptomatic and is there is reason to add an additional rate control drug,
not receiving optimal therapy. Although the patient is such as digoxin (Answer B) or diltiazem (Answer
NYHA class III, no rationale exists for adding spirono- A). With his PAD, atorvastatin therapy is necessary,
lactone at this time because she is not receiving optimal making Answer C incorrect. In addition, his BP is
HF therapy (Answer C). well controlled; therefore, increasing the lisinopril
dose is not warranted, making Answer B incorrect.
2. Answer: C To derive the beneficial antiplatelet effects for CV
This patient is taking the target dose of enalapril; fur- event prevention, aspirin 81 mg is adequate. Aspirin
ther increases in the enalapril dose are unnecessary 325 mg/day is also effective, but has a greater risk of
unless the patient is hypertensive (Answer B). Adding bleeding with concomitant apixaban. Therefore, adding
β-blocker therapy, initially at a low dose, together with apixaban and decreasing the dose of aspirin to 81 mg/
ACE inhibitor therapy, is recommended for further day (Answer D) is correct.
reductions in morbidity and mortality and for slowing
the progression of HF (Answer C). Digoxin is indicated 5. Answer: A
only in symptomatic patients, despite optimal therapy, This patient is experiencing a rapid ventricular response
and this patient’s pharmacotherapy has not been opti- with exercise or strenuous activity, causing the sensa-
mized, making Answers A and D incorrect. tion of palpitations and dyspnea. Digoxin alone poorly
controls the ventricular rate during times of high sym-
3. Answer: D pathetic influence (e.g., exercise). Additional therapy is
This patient has HFpEF, which is caused by a problem usually necessary to control the ventricular rate ade-
with ventricular relaxation. Treatment of HFpEF quately. A β-blocker such as metoprolol succinate is a
includes managing risk factors such as HTN and opti- good choice to maintain HR during activity (Answer
mizing HF pharmacotherapy. The most recent HF A). Using verapamil with digoxin in this patient could
guidelines recommend consideration of SGLT2 inhib- result in signs or symptoms of toxicity, given his cur-
itors for patients with HFpEF and adequate renal func- rent digoxin concentration. In addition, he is already
tion, making Answer D correct. SGLT2 inhibitors might taking a CCB, making verapamil a less desirable
result in slight reductions in the patient’s blood pres- choice (Answer C). Similarly, doubling the digoxin
sure, but additional blood pressure control may be war- dose would almost double the current serum concentra-
ranted in the future. Answer A is incorrect because the tion to 2.2 ng/dL, which should be avoided (Answer B).
patient’s heart rate is not elevated, and metoprolol suc- Instructing the patient to avoid activity is undesirable
cinate is not mortality reducing in HFpEF. Furosemide because physical activity should be encouraged and
is not warranted because of lack of volume overload, supported in all patients, especially in those with risk
making Answer B incorrect. Although spironolactone factors for CV disease (Answer D).

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6. Answer: A 9. Answer: D
According to the ACC/AHA guidelines, this patient’s BP Secondary causes of hypertriglyceridemia should be
should be treated to a goal of less than 130/80 mm Hg ruled out when TG concentrations are greater than
because he has no clinical CVD and a 10-year ASCVD 500 mg/dL or when LDL-C is greater than 190 mg/dL.
risk ≥10%, making answers B and D incorrect. Beta block- Different medications, conditions, and diet can affect
ers are not recommended first-line for HTN management these lipid values. Although obesity, poorly controlled
in the absence of coronary artery disease, heart failure, DM, olanzapine, and metoprolol can increase TG con-
or atrial fibrillation, making answer C incorrect. Answer centrations, coenzyme Q does not affect TG; therefore,
A includes a first-line HTN medication which also main- Answer A is incorrect. Alcohol consumption, poorly
tains efficacy in the African American population. controlled DM, and β-blockers can all increase TG,
but weight loss does not increase TG. Weight loss can
7. Answer: D actually lower LDL-C and TG; therefore, Answer B is
This patient has been identified as being at risk of incorrect. Although obesity and alcohol consumption
ASCVD, according to his pooled cohort equation result can elevate TG, neither CCBs nor hyperthyroidism are
of 14.6%. Therefore, the patient falls into one of the four expected to have this effect (Answer C is incorrect). All
patient management groups (age 40–75 years with an the conditions, medications, or disease states in Answer
LDL-C of 70–189 mg/dL and a 10-year ASCVD risk D can increase TG, making this option correct.
of 7.5-19.9% without DM or ASCVD) and thus should
be initiated on statin therapy. According to the guide- 10. Answer: D
lines, this patient should be treated with moderate- to Oral contraceptives, specifically estrogen, can increase
high-intensity statin therapy. Although simvastatin BP, especially with a longer duration of use. An alter-
20 mg is considered a moderate-intensity dose, adding native contraceptive without estrogen would be less
gemfibrozil to this patient’s regimen would be inappro- likely to contribute to her HTN (Answer D is cor-
priate because gemfibrozil is contraindicated in com- rect). Answers A and B are incorrect because her BP
bination with simvastatin; also, his TG concentrations requires better control, but weight loss is unlikely to
are less than 500 mg/dL and need not be specifically help because her BMI is normal. Answer C is incorrect
targeted (Answer A). Using pravastatin 20 mg would because hydrochlorothiazide is no more potent than
be inappropriate because this is considered a low- chlorthalidone.
intensity dose, and it would not provide the more than
30%–50% reduction in LDL-C that is recommended. 11. Answer: B
In addition, fenofibrate would not be needed because his ACE inhibitor therapy is contraindicated in pregnancy,
TG concentrations are lower than 500 mg/dL (Answer and discontinuing ramipril is the most important next
C). Rosuvastatin 2.5 mg is a low-intensity dose and step, making Answers A and C incorrect. Answer D is
would not be appropriate (Answer B). Atorvastatin 20 incorrect because this patient will require good BP con-
mg is considered a moderate-intensity dose, and it will trol during her pregnancy. Labetalol is a good choice of
provide a 30%-50% reduction in LDL-C, as is recom- therapy because it is a preferred antihypertensive drug
mended (Answer D). in pregnancy (Answer B is correct).

8. Answer: D 12. Answer: D

This patient is 40–75 years of age and does not have Because the patient has CHD, his options for antiar-
ASCVD, severe hypercholesterolemia, or DM. rhythmic therapy are limited. Class Ic antiarrhyth-
Therefore, he is in the statin treatment group of primary mic drugs are contraindicated in patients with CHD;
prevention. His 10-year ASCVD risk of 3.9% indicates therefore, flecainide and propafenone cannot be used
he is considered at low risk. Statin therapy is not indi- (Answers B and C are incorrect). Disopyramide, a class
cated at this time (Answers A and C are incorrect), and Ia antiarrhythmic, is not a preferred therapy for AF;
only lifestyle modifications are indicated. He should therefore, Answer A is incorrect. Sotalol, a class III
be reassessed in 4–6 years (Answer D is correct). The antiarrhythmic, can be used in patients with CHD and
patient’s TGs are normal, so treatment with a fibrate is good renal function; therefore, Answer D is correct.
not necessary at this time (Answer B is incorrect).

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