ACCP_Updates_in_Therapeutics®_2023_Pharmacotherapy_Preparatory_Review-1 copy_extract_1.pdf

Acute Care in Cardiology 2. β-Blockers a. Indicated for all patients unless contraindicated b. If not initiated orally within the first 24 hours, reevaluate for possible initiation before discharge. c. It is unclear the ideal duration of β-Blockers post-MI unless there is a compelling indic...

Acute Care in Cardiology 2. β-Blockers a. Indicated for all patients unless contraindicated b. If not initiated orally within the first 24 hours, reevaluate for possible initiation before discharge. c. It is unclear the ideal duration of β-Blockers post-MI unless there is a compelling indication. d. If moderate or severe LV failure, initiate carvedilol, bisoprolol, or metoprolol succinate with gradual titration. Continue indefinitely in patients with an EF less than 40%. 3. Angiotensin-converting enzyme (ACE) inhibitors a. ACE inhibitors should be initiated and continued indefinitely for all patients with an LVEF of 40% or less and in those with hypertension, diabetes mellitus, or stable chronic kidney disease, unless contraindicated. b. ACE inhibitors may be acceptable in all other patients with cardiac or other vascular disease. c. Angiotensin receptor blockers (ARBs) are indicated if the patient has contraindications to or is intolerant of ACE inhibitors. d. Contraindications include hypotension, pregnancy, and bilateral renal artery stenosis. Table 12. DAPT Score to Determine Favorability of Prolonged DAPT Factors Used to Calculate DAPT Score Age ≥ 75 Age 65–74 Current tobacco user Diabetes mellitus NSTEMI or STEMI at presentation Prior MI or PCI Stent diameter < 3 mm Paclitaxel-eluting stent CHF or LVEF < 30% Saphenous vein graft PCI Add Points for Total Scorea -2 -1 1 2 2 A score ≥ 2 favors prolonged DAPT; a score < 2 is of unfavorable risk-benefit. CHF = congestive heart failure; DAPT = dual antiplatelet therapy; LVEF = left ventricular ejection fraction. Information from: 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; and Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735-49. a 4. Aldosterone receptor blockers a. Indicated in patients who are already receiving an ACE inhibitor and β-blocker after MI and who have an LVEF of 40% or less and either symptomatic HF or diabetes, unless contraindicated b. Contraindications include hyperkalemia (potassium [K+] 5.0 or greater), CrCl less than 30 mL/ minute, and SCr greater than 2.5 mg/dL in men and greater than 2.0 mg/dL in women. 5.  Lipid-lowering therapies a. High-intensity statins are indicated in all patients after ACS without contraindication and are generally initiated as soon as possible within the first 24 hours. b. In high-risk patients achieving a less-than-expected response to statins (less than a 50% reduction in low-density lipoprotein cholesterol [LDL]), or in those who are completely statin intolerant, non-statin therapy may be considered for CV benefit. c. Depending on the additional desired LDL percentage reduction, either ezetimibe or a PCSK9 inhibitor can be considered in combination with statin therapy in very high-risk patients. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-25 Acute Care in Cardiology d. Both ezetimibe and PCSK9 inhibitors (given in combination with statins) reduce CV end points. e. PCSK9 inhibitors therapy has been associated with significant reduction of MACE in post-ACS patients. This seems to be achieved both directly through a process of modification in plaque composition with its subsequent stabilization and indirectly by intervening in lipid metabolism and platelet aggregation. Early introduction of PCSK9 inhibitor therapy for a more aggressive approach to prevent MACE events may be considered given that the risk for cardiovascular events remains high within the first year of ACS, but must be weighed against cost considerations. f. An LDL goal of less than 70 mg/dL is reasonable in patients post-ACS. 6. Pain control a. NSAIDs and select cyclooxygenase-2 inhibitors (class III) should be discontinued at the time of presentation because they have been associated with an increased risk of major adverse cardiac events. b. Before discharge, the patient’s musculoskeletal discomfort should be addressed, and a stepped-care approach should be used to select therapy. c. Pain should be treated with acetaminophen, nonacetylated salicylates, tramadol, or narcotics at the lowest dose to control symptoms. d. It is reasonable to use nonselective NSAIDs, such as naproxen, if initial therapy is insufficient. i. Monitor regularly for sustained hypertension, edema, worsening renal function, or GI bleeding. ii. If these occur, consider dose reduction or discontinuation. 7. Vaccination a. Pneumococcal vaccination is recommended for patients 65 and older and in high-risk patients (including smokers with asthma) with CV disease. b. An annual influenza vaccination is recommended for patients with CV disease. 8. Patient education a. All patients should be counseled on the duration of DAPT and the avoidance of premature discontinuation, especially in the first few days following PCI, when risk of stent thrombosis is highest. b. Patients should be educated about appropriate cholesterol management, blood pressure control, smoking cessation, and lifestyle management. c. Risk factor modification should be addressed in all patients after ACS. 9. Cardiac rehabilitation: All eligible patients should be referred to a comprehensive CV rehabilitation program. 10. Low-dose direct acting oral anticoagulant a. While data exist to consider the use of low-dose rivaroxaban to reduce the risk of CV mortality, MI, or stroke, current guidelines do not support routine use for patients with recent ACS. b. The COMPASS trial explored use for rivaroxaban 2.5 mg two times a day in addition to low dose aspirin in adults with stable CAD and found an associated absolute risk reduction of about 1% in a combined CVD endpoint, which was offset by an increased rate of major bleeding of about 1% compared with aspirin alone. E. Special Populations 1. Antiplatelet recommendations in patients going on to CABG a. Aspirin should be continued preoperatively to patients undergoing CABG (81–325 mg). b. In patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least 3–5 days before surgery and prasugrel for at least 7 days before surgery. c. In patients referred for urgent CABG, clopidogrel and ticagrelor should be discontinued for at least 24 hours to reduce major bleeding. d. In patients referred for CABG, short-acting GP IIb/IIIa inhibitors (eptifibatide or tirofiban) should be discontinued for at least 2–4 hours before surgery to limit blood loss and transfusion. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-26 Acute Care in Cardiology 2. Combined oral anticoagulant therapy and antiplatelet therapy in patients with atrial fibrillation (AF) undergoing PCI a. Triple therapy with an oral anticoagulant, low-dose aspirin, and a P2Y12 inhibitor should be minimized because it substantially increases the risk of bleeding. b. New AF guidelines and consensus recommendations based on clinical trial data represent a paradigm shift from older management with triple therapy: i. Many trials have shown that double antithrombotic therapy (anticoagulant plus P2Y12 inhibitor without aspirin) reduces bleeding events compared with triple therapy without signal for increasing ischemic events. (a) Double therapy with a P2Y12 inhibitor plus dose-adjusted vitamin K antagonist (WOEST trial) (b) Double therapy with a P2Y12 inhibitor plus rivaroxaban 15 mg daily (PIONEER AF) (c) Double therapy with a P2Y12 inhibitor plus dabigatran 150 mg twice daily (RE-DUAL) (d) Double therapy with a P2Y12 inhibitor plus apixaban 5 mg twice daily (AUGUSTUS) ii. De-escalation time from triple to dual therapy varies depending on ischemic and bleeding risks. (a) Aspirin therapy can be discontinued at time of discharge or can be continued for 1–3 months, depending on risks. One analysis of stent thrombosis rates suggested that 80% of events occur within 30 days of PCI; therefore, it may be reasonable to prolong aspirin therapy to 1 month to reduce the rates of stent thrombosis in those felt to be high risk. (b) Triple therapy may be extended beyond hospital discharge for a limited time (i.e., 1–3 months) in select patients at the highest risk of ischemic events and lowest risk of bleeding. iii. In AF, direct-acting oral anticoagulants are preferred to vitamin K antagonists because of their reduced bleeding risk. (a) Warfarin remains the drug of choice in patients with mechanical heart valves and in those with moderate to severe mitral stenosis. (b) If warfarin is used for triple therapy, it is reasonable to maintain the international normalized ratio (INR) at the lower end of the therapeutic range (i.e., 2–2.5). iv. Clopidogrel is the preferred P2Y12 inhibitor, though ticagrelor may be reasonable in patients at high ischemic/thrombotic and low bleeding risks (i.e., avoid prasugrel). (a) Discontinue antiplatelet therapy at 1 year in most patients. (b) However, the same considerations apply for shortening the duration (i.e., 6 months in those with high bleeding risk) and extending the duration (i.e., more than 12 months in those at high thrombotic risk with low bleeding risk) as for those without AF. c. Proton pump inhibitors should be considered for those with a history of GI bleeding (and is reasonable in those without a known history of GI bleeding) who need triple antithrombotic therapy. 3. Older patients (i.e., 75 or older) a. Doses should be individualized by weight or CrCl to reduce adverse events caused by age-related changes in pharmacokinetics and dynamics, volume of distribution, comorbidities, drug interactions, and increased drug sensitivity. b. Bivalirudin, rather than GP IIb/IIIa inhibitors plus UFH, is reasonable in older patients, given its similar efficacy but less risk of bleeding (class IIb). c. If enoxaparin is used as an anticoagulant in older patients (older than 75), the bolus should be omitted, and the dosing strategy should be 0.75 mg/kg subcutaneously every 12 hours; should not exceed 75 mg for the first two doses d. CABG may be preferred to PCI in older patients, particularly those with diabetes mellitus or complex three-vessel disease (e.g., SYNTAX score greater than 22), with or without involvement of the proximal left anterior descending artery. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-27 Acute Care in Cardiology 4. Chronic kidney disease a. CrCl should be estimated in patients with ACS, and doses of renally cleared medications should be adjusted accordingly. b. Patients with chronic kidney disease undergoing coronary and LV angiography should receive adequate hydration and reduced contrast volume. 5. Women a. Women of all ages have higher rates of in-hospital and long-term complications from ACS than men. b. Women derive the same benefit from aspirin, P2Y12 inhibitors, anticoagulants, β-blockers, ACE inhibitors, and statins as men, but women may be at higher risk of adverse events. i. Women have a higher rate of bleeding complications, renal failure, and vascular complications. ii. A risk score has been developed to reduce bleeding risk. c. Women with NSTE-ACS and high-risk features (e.g., troponin positive) should undergo an early invasive strategy. d. Women with NSTE-ACS and low-risk features should not undergo early invasive treatment because of the lack of benefit and the potential for harm (class III). e. Hormone therapy with estrogen plus progestin, or estrogen alone, should not be initiated for secondary prevention and should not be continued in previous users unless the benefits outweigh the estimated risks. i. Hormone therapy increases the risk of thrombotic events, especially in the first year of therapy, and does not provide CV protection. ii. Women who are more than 1 year past the initiation of hormone therapy who want to continue such therapy for another compelling indication should weigh the risk-benefit, recognizing the greater risk of CV events and breast cancer (combination therapy) or stroke (estrogen). Patient Cases 1. A 66-year-old woman (weight 70 kg) with a history of MI, hypertension, hyperlipidemia, and diabetes mellitus presents with sudden-onset diaphoresis, nausea, vomiting, and dyspnea, followed by a bandlike upper chest pain (8/10) radiating to her left arm. She had felt well until 1 month ago, when she noticed her typical angina was occurring with less exertion. Her ECG reveals ST-segment depression in leads II, III, and aVF and hyperdynamic T waves and positive cardiac enzymes. Blood pressure is 150/90 mm Hg, and all laboratory results are normal; SCr is 1.2 mg/dL. Home medications are aspirin 81 mg/day, simvastatin 40 mg every night, metoprolol 50 mg twice daily, and metformin 1 g twice daily. Which regimen is best for this patient? A. Aspirin 325 mg, ticagrelor 180 mg one dose, and UFH 60-unit/kg bolus; then 12 units/kg/hour titrated to 50–70 seconds with an early invasive approach. B. Aspirin 325 mg and enoxaparin 70 mg subcutaneously twice daily with an early invasive approach. C. A  n ischemia-guided strategy with tirofiban 25 mcg/kg; then 0.15 mg/kg/minute plus enoxaparin 80 mg subcutaneously twice daily, aspirin 325 mg/day, and clopidogrel 300 mg one dose; then 75 mg once daily. D. An ischemia-guided strategy with aspirin 325 mg and ticagrelor 180 mg one dose; plus UFH 70-unit/kg bolus; then 15 units/kg/hour. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-28 Acute Care in Cardiology II. ACUTE DECOMPENSATED HEART FAILURE A. Precipitating Factors 1. Medication related (nonadherence to medications, recent addition of negative inotropic drugs, initiation of medications that enhance salt retention, excessive alcohol or illicit drug use) 2. Disease related (nonadherence to sodium or fluid restriction, acute myocardial ischemia, uncorrected high blood pressure, pulmonary embolus, AF or other arrhythmias, concurrent infections, other acute CV disorders) B. Diagnosis 1. Must include a detailed history and physical examination 2. B-type natriuretic peptide (BNP) or NT-proBNP is useful to support the diagnosis and establish the prognosis for acute decompensated heart failure (ADHF). a.  Useful for excluding ADHF in patients with dyspnea of unknown etiology (ADHF can be excluded when results are less than 100 pg/mL and less than 300 pg/mL, for BNP and NT-proBNP, respectively) b. NT-proBNP cutpoints of 450, 900, and 1800 pg/mL (for ages younger than 50, 50–75, and older than 75, respectively) c. May be elevated with older age, female sex, renal dysfunction, and other cardiopulmonary disorders like pulmonary embolism d. NT-proBNP is preferred in patients receiving angiotensin receptor neprilysin inhibitor (ARNI) therapy because BNP concentrations may be affected by ARNI therapy 3. Hemodynamic monitoring (Table 13) a. Routine use of hemodynamic monitoring with invasive intravenous lines (e.g., Swan-Ganz pulmonary artery catheters) is not recommended; however, signs and symptoms of congestion and perfusion (Table 14) or noninvasive means to determine hemodynamic values are commonly used to determine status of decompensation. b. Hemodynamic monitoring with pulmonary artery catheters helps in evaluating patients refractory to initial therapy, patients with unknown or unclear volume status, and patients with clinically significant hypotension or worsening renal function. c. Use of hemodynamic monitoring for mechanical circulatory support is beyond the scope of this chapter. Table 13. Hemodynamic Values in Patients with ADHF and Sepsis Normal Value 80–100 60–80 4–7 2.8–3.6 8–12b 900–1400 2–6 Parameter Mean arterial pressurea (MAP; mm Hg) Heart rate (HR; beats/min) Cardiac output (CO; L/min)b Cardiac index (CI; L/min/m2)c Pulmonary capillary wedge pressure (mm Hg)d Systemic vascular resistance (SVR; dynes/s/cm5)e Central venous pressure (CVP; mm Hg) Typical ADHF Value 60–80 70–90 2–4 1.3–2 18–30 1500–3000 6–15 Typical Sepsis Value 60–80 90–100 5–8 3.5–4 5–8 300–800 2–6 BP = CO × SVR. a MAP = diastolic blood pressure (DBP) + [⅓(SBP − DBP)]. b CO = stroke volume × HR. c CI = CO/body surface area. d 15–18 mm Hg is often desired or optimal in patients with HF to ensure optimal filling pressures. e SVR = [(MAP − CVP)/CO] × 80. ADHF = acute decompensated heart failure; SVR = systemic vascular resistance. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-30 Acute Care in Cardiology C. Clinical Presentation 1. Patients with ADHF can be categorized into four subsets on the basis of fluid status and cardiac function (Figure 2). 2. “Wet or dry” is commonly used to describe volume status. 3. “Warm or cold” is used to describe cardiac function or ability to perfuse tissues. Table 14. Signs and Symptoms of ADHF Congestion (elevated PCWP) Hypoperfusion (low CO) Dyspnea on exertion or at rest Orthopnea, paroxysmal nocturnal dyspnea Peripheral edema Rales Early satiety, nausea, or vomiting Ascites Hepatomegaly, splenomegaly Jugular venous distension Hepatojugular reflux Fatigue Altered mental status or sleepiness Cold extremities Worsening renal function Narrow pulse pressure Hypotension Cardiac index (L/minute/m2 CO = cardiac output; PCWP = pulmonary capillary wedge pressure. 4 3 2 1 Category I: Compensated Warm and Dry Category III: Hypoperfusion Cold and Dry 10 Category II: Pulmonary congestion Warm and Wet Category IV: Pulmonary congestion and hypoperfusion Cold and Wet 15 20 PCWP (mm Hg) 25 Figure 2. Forrester hemodynamic subsets based on signs and symptoms or hemodynamic parameters in acute decompensated heart failure. PCWP = pulmonary capillary wedge pressure. D. ADHF Therapy Overview (Box 1; Table 15) 1. Address any precipitating factors, when possible. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-31 Acute Care in Cardiology Box 1. Overview of ADHF Guideline Recommendations Diuretic therapy Recommended as IV loop diuretics for patients with fluid overload. Change to PO route on day before discharge, if possible When response to diuretics is minimal, the following options should be considered: • Fluid and sodium restriction • Initiation of increased doses or continuous infusion of loop diuretic • Addition of a second diuretic with a different mechanism of action (metolazone, chlorothiazide, acetazolamide) • Ultrafiltration Inotropic therapy May be considered to relieve symptoms and improve end-organ function in patients with reduced LVEF and diminished peripheral perfusion or end-organ dysfunction (low output syndrome), particularly if • Marginal SBP (< 90 mm Hg) • Symptomatic hypotension despite adequate filling pressure • No response to or intolerance of IV vasodilators  ay be considered in similar patients with evidence of fluid overload if they respond poorly to IV diuretics M or manifest diminished or worsening renal function Vasodilator therapy May be considered in addition to IV loop diuretics to rapidly improve symptoms in patients with acute pulmonary edema or severe hypertension (if symptomatic hypotension absent) May be considered in patients with persistent symptoms despite aggressive diuretics and PO drug therapy  hen adjunctive therapy is necessary in addition to loop diuretics, IV vasodilators should be considered W over inotropic drugs ADHF = acute decompensated heart failure; IV = intravenous(ly); LVEF = left ventricular ejection fraction. 2. 3. 4. Relieve signs and symptoms of congestion and tissue hypoperfusion. a. The main drug classes used to treat ADHF include diuretics, inotropes, and vasodilators. b. No therapy studied to date has been shown conclusively to decrease mortality. c. Treatments are directed toward relieving symptoms, restoring perfusion, and minimizing further cardiac damage and adverse events and are guided by cardiac output (CO) and volume status. Reduce in-hospital mortality and minimize risk of rehospitalization. Optimize GDMT. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-32 Acute Care in Cardiology Table 15. General ADHF Management Based on Hemodynamic Subseta Subset and Description Treatment Subset I: Warm and Dry (normal parameters) (PCWP 15–18 mm Hgb and CI > 2.2 L/min/m 2) Optimize guideline-directed medical therapies (PO medications) Subset II: Warm and Wet (pulmonary or peripheral congestion) (PCWP > 18 mm Hg and CI > 2.2 L/min/m 2) IV diuretics at a dose that equals or exceeds pre-admission dose (up to 2.5-fold) ± IV vasodilators (venousc) for rapid relief of pulmonary congestion or (arterial) in the absence of hypotension If symptoms persist, adjunctive strategiesd to overcome diuretic resistance may be necessary Subset III: Cold and Dry (hypoperfusion ± orthostasis) (PCWP 15–18 mm Hgb and CI < 2.2 L/min/m 2) If PCWP < 15 mm Hg, IVF until PCWP = 15–18 mm Hg If PCWP ≥ 15 mm Hg, SBP < 90 mm Hg, IV inotropee If PCWP ≥ 15 mm Hg, SBP ≥ 90 mm Hg, IV vasodilator (arterialf ) ± IV vasopressor,g if needed Subset IV: Cold and Wet IV diuretics + (pulmonary/peripheral congestion + hypoperfusion) If SBP ≥ 90 mm Hg, IV vasodilator (arterialf ) (PCWP > 18 mm Hg and CI < 2.2 L/min/m 2) If SBP < 90 mm Hg, IV inotropee ± IV vasopressor,g if needed Patients may be categorized into a hemodynamic subset on the basis of signs and symptoms or invasive hemodynamic monitoring. Goal PCWP is 8–12 mm Hg in a normal patient and 15–18 mm Hg in a patient with HF. If PCWP < 15 mm Hg in a patient with HF, either remove fluid restriction or cautiously administer fluids until PCWP is 15–18 mm Hg and then reassess CI. c Venous vasodilator: Reduces PCWP. d Adjunctive strategies for overcoming diuretic resistance include increasing the loop diuretic dose; changing to a continuous infusion; adding a diuretic with an alternative mechanism of action, an IV vasodilator, or an IV inotrope; and, in select patients, using ultrafiltration or a vasopressin antagonist. e Compelling reason for inotrope = SBP < 90 mm Hg, symptomatic hypotension, or worsening renal function. f Arterial vasodilator: Reduce systemic vascular resistance with compensatory increase in CI. g IV vasopressors may be required when marked hypotension precludes the use of traditional IV inotropes (e.g., septic or cardiogenic shock) but are generally avoided in ADHF. CI = cardiac index; IV = intravenous(ly); IVF = intravenous fluid; PCWP = pulmonary capillary wedge pressure; PO = oral(ly). a b E. Chronic HF Therapy in the Setting of Acute Decompensation 1. It is recommended to continue guideline-directed medical therapies (GDMTs) during decompensation unless hemodynamic instability or contraindications exist (e.g., hypotension, cardiogenic shock) because discontinuing GDMT worsens outcomes. a. In patients experiencing mild decrease of renal function or asymptomatic reduction of blood pressure during HF hospitalization, diuresis and other GDMT should not routinely be discontinued (Class I). b. In patients with HFrEF, if discontinuation of GDMT is necessary during hospitalization, it should be reinitiated and further optimized as soon as possible (Class I). c. In patients with HFrEF, GDMT should be initiated during hospitalization after clinical stability is achieved (Class I). 2. ACE inhibitors/ARBs, ARNIs a. Caution with initiation or titration during aggressive diuresis b. Increases in SCr (decrease in glomerular filtration rate of 20% or more) from ACE inhibitor use are not associated with worse outcomes. c. Consider discontinuation if worsening renal function after recent drug initiation or increased symptomatic hypotension, severe hyperkalemia (K greater than 5.5 mEq/L) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-33 Acute Care in Cardiology 3. β-Blockers a. Do not discontinue in patients whose condition is stable on dose before admission (i.e., recent initiation or titration was not responsible for decompensation). i. In OPTIMIZE-HF, discontinuation of beta blockers was associated with a higher risk of mortality compared with those continued on β blockers. b. Consider discontinuation if ADHF caused by recent drug initiation or increase, evidence of new or worsening low output or cardiogenic shock, symptomatic hypotension or bradycardia. i. Withholding or reducing β-blocker therapy should be considered in patients with marked volume overload or marginal low cardiac output. c. Initiation is recommended after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. d. Should be initiated at a low dose only in stable, euvolemic patients e. Caution should be used when initiating in patients who have received inotropes during their hospital course. 4. Mineralocorticoid antagonists a. Do not discontinue in patients whose condition is stable on dose before admission b. Consider dose-reduction or discontinuation in the setting of hyperkalemia 5. SGLT2 Inhibitors a. Do not discontinue in patients whose condition is stable on dose before admission b. Temporary discontinuation for acute kidney injury when GFR falls below the cut-offs for individual use 6. Digoxin a. Continue at dose to achieve serum digoxin concentration of 0.5–0.8 ng/mL. b. Consider discontinuation in symptomatic bradycardia, life-threatening arrhythmias, elevated concentrations, or signs/symptoms of digoxin toxicity. c. Avoid discontinuation unless there is a compelling reason to do so, because digoxin withdrawal has been associated with worsening HF symptoms. d. Caution if renal function begins to deteriorate or often fluctuates F. Diuretics (Box 2; Table 16): Used primarily to treat patients with pulmonary and peripheral congestion or wet (subset II or IV) HF 1. Considered first-line therapy for management of ADHF associated with fluid overload to improve symptoms and reduce morbidity. 2. No difference between bolus and continuous administration of intravenous diuretics 3. Administering high-dose intravenous diuretic (2.5 times the previous oral dose) is associated with greater fluid removal. 4. In patients hospitalized with HF when diuresis is inadequate to relieve symptoms and signs of congestion, it is reasonable to intensify the diuretic regimen using either higher doses of intravenous loop diuretics or addition of a second diuretic. 5. For patients requiring diuretic treatment during hospitalization for HF, the discharge regimen should include a plan for adjustment of diuretics to decrease rehospitalizations (Class I). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-34 Acute Care in Cardiology Box 2. Diuretic Therapy for ADHF Loop diuretics (ascending limb of loop of Henle) Most widely used and most potent, effective at low CrCl (< 30 mL/min) Furosemide most commonly used; furosemide 40 mg PO = furosemide 20 mg IV = bumetanide 1 mg IV or PO = torsemide 20 mg PO Thiazides or thiazide-like diuretics (distal tubule) Weak diuretics when used alone, less effective at low glomerular filtration rate (CrCl < 30 mL/min) Reserved for add-on therapy when refractory to loop diuretics Acetazolamide (proximal tubule) Recommended as adjunct to intravenous loop diuretics May be administered as an IV dose of 500 mg once daily to improve diuresis, naturesis, and decongestion Diuretic resistance Increase dose before increasing frequency of loop diuretic (note ceiling effect at ~160–200 mg of IV furosemide) Add a second diuretic with a different mechanism of action • Metolazone 2.5–5 mg PO daily (30 min before loop diuretic administration) •  hlorothiazide 250–500 mg IV daily; consider if GI edema; generic is expensive; reserve for NPO or C refractory to other alternatives Continuous infusion of loop diuretic: Furosemide 5–20 mg/hr, up to a maximum of 40 mg/hr. IV bolus doses should be given with the start of infusion and with rate increases to achieve steady state more quickly. Adverse effects: Electrolyte depletion (sodium, K+, magnesium), worsening renal function GI = gastrointestinal; NPO = nothing by mouth. Table 16. Loop Diuretic Pharmacokinetic and Pharmacodynamic Comparisons Drug PO equivalent dose Bioavailability, % PO to IV conversion Usual maintenance dose Ceiling dose (normal CrCl) Onset (peak), PO Onset of action (IV) Metabolism Half-life normal (HF) Avg duration of effect Furosemide 40 mg 10%–100% (avg 50%) 2:1 40–160 mg ~160 mg 30–60 min (1 hr) 5 min 50% renal conjugation 1.5–2 hr (2.7 hr) 6–8 hr Bumetanide 1 mg 80%–100% 1:1 1–5 mg 1–2 mg 30–60 min (1–2 hr) 2–3 min 50% hepatic 1 hr (1.3 hr) 4–6 hr Torsemide 20 mg 70%–100% 1:1 10–20 mg 10–20 mg 60 min 10 min 80% hepatic 3–4 hr (6 hr) 12–16 hr Ethacrynic Acid 50 mg 100% 1:1 25–50 mg ~200 mg 30 min 5 min 66% renal 1–4 hr 6 hr avg = average. G. Vasodilator Therapy (Table 17) 1. Used (with diuretics) primarily to manage pulmonary congestion or wet (subset II or IV) HF a. Use is limited to relief of dyspnea in those with intact blood pressure. b. Vasodilator therapy may improve dyspnea symptoms and relieve pulmonary congestion; however, their benefits have not been shown to have durable effects for either rehospitalization or mortality benefit. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-35 Acute Care in Cardiology 2. 3. When adequate blood pressure is maintained, use in preference to inotropic therapy. Venodilators increase venous capacitance, resulting in lower preload to reduce myocardial stress. a. Limits ischemia and helps preserve cardiac tissue (i.e., nitroglycerin would be the drug of choice for patients with ADHF and active ischemia) b. Produces rapid symptomatic benefit by reducing pulmonary congestion (i.e., acute relief of shortness of breath while awaiting the onset of diuretic effects) c. Nitroglycerin is commonly used as a venodilator, particularly for those with hypertension, coronary ischemia, and significant mitral regurgitation. i. Tachyphylaxis may develop within 24 hours, and up to 20% of those with HF may develop resistance despite increasing doses of nitroglycerin. 4. Vasodilators with arterial vasodilating properties (nitroprusside) can also be used as an alternative to inotropes in patients with elevated systemic vascular resistance (SVR) and low CO. a. Sodium nitroprusside has marked potential for producing profound hypotension and is usually reserved for patients: i. With invasive hemodynamic monitoring (i.e., pulmonary artery catheter, arterial blood pressure monitoring) ii. Without end-organ dysfunction (i.e., to avoid cyanide and thiocyanate accumulation) iii. Only until hemodynamic stabilization is achieved iv. To ensure the reversibility of pulmonary hypertension during evaluation for mechanical circulatory support or transplantation v. Avoid use in patients with active ischemia/ACS because of risk for coronary steal syndrome. b. Nesiritide was discontinued by the manufacturer in February 2018. 5. Vasodilators should be avoided in patients with symptomatic hypotension (i.e., SBP less than 90 mm Hg). 6. Frequent blood pressure monitoring is necessary. Table 17. Vasodilator Therapy for ADHF Mechanism of action Sodium Nitroprusside (Nipride) Nitric oxide–induced stimulation of GC to convert GTP to cGMP Clinical effects Balanced arterial and venous vasodilator Indication Dosing Typical dose Half-life Elimination AEs Warm and wet ADHF, alternative to inotropes in cold and wet ADHF, hypertensive crises 0.1–0.2 mcg/kg/min IV, increase by 0.2–3 mcg/kg/min every 5 min; max dose 10 mcg/ kg/min not to be used for more than 10 min 0.5–1 mcg/kg/min IV; rarely need more than 4 mcg/kg/min 2 min Cyanide hepatically metabolized, thiocyanate renally excreted Hypotension or cyanide or thiocyanate toxicity IV Nitroglycerin Combines with sulfhydryl groups in vascular endothelium to create S-nitrosothiol compounds that mimic nitric oxide’s stimulation of GC and production of cGMP Preferential venous vasodilator greater than arterial vasodilator; arterial vasodilation at high doses Warm and wet ADHF, ACS, or hypertensive crises 5 mcg/min IV, increase by 5 mcg/min every 5–10 min up to 200 mcg/min 25–100 mcg/min IV, titrated to response 1–3 min Inactive metabolites in urine Hypotension, reflex tachycardia, headache, tachyphylaxis AE = adverse effect; cGMP = cyclic guanine monophosphate; GC = guanylate cyclase; GTP = guanosine triphosphate. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-36 Acute Care in Cardiology H. Inotropic Therapy (Table 18) 1. Used primarily to manage hypoperfusion or cold (subset III or IV) HF a. Useful for symptom relief in patients with a low SBP (less than 90 mm Hg) or symptomatic hypotension b. For patients in cardiogenic shock, inotropic therapy should be used to maintain systemic perfusion and preserve end-organ function (Class I). c. Useful in patients whose disease is refractory to other HF therapies d. Useful as a bridge to an LV assist device or to a heart transplant or as palliative care 2. It is important to confirm that patients in subset III have adequate filling pressures (i.e., pulmonary capillary wedge pressure [PCWP] 15–18 mm Hg) before administering inotropic therapy. 3. Given the risk of sequelae, it is reasonable to consider vasodilators before inotropes. a. Both milrinone and dobutamine are proarrhythmic. b. Inotropes increase mortality compared with vasodilator therapy. 4. Monitor continuously for arrhythmias. 5. Differences in the pharmacologic effects of dobutamine and milrinone may confer advantages and disadvantages, but the choice of inotropic therapy is very individualized. a. Milrinone may be favored: i. To avoid tapering or discontinuing home β-blocker ii. When pulmonary artery pressures are high b. Dobutamine may be favored in: i. Severe hypotension ii. Bradycardia iii. Thrombocytopenia iv. Severe renal impairment Table 18. Inotropic Therapy for ADHF Mechanism of action Clinical effects Indication Dosing Typical dose Half-life Elimination AEs Other comments Dobutamine (Dobutrex) β1-Agonist: Stimulates AC to convert ATP to cAMP to ↑ CO; slight peripheral vasodilation Milrinone (Primacor) PDE inhibitor: Inhibits cAMP breakdown in heart to ↑ CO and in vascular smooth muscle to ↓ SVR Positive inotropic, chronotropic, lusitropic Positive inotropic and lusitropic effects, effects no direct chronotropic effects ADHF: Cold and wet (Forester subset IV) or cold and dry exacerbations (Forester III) (if PCWP > 15 mm Hg) Start 2.5–5 mcg/kg/min IV; may titrate to 0.125–0.25 mcg/kg/min IV; may titrate to max max of 20 mcg/kg/min of 0.75 mcg/kg/min 5 mcg/kg/min IV No bolus, 0.1–0.375 mcg/kg/min IV 2 min 1 hr, prolonged to 2–3 hr if HF or CrCl < 50 mL/min; may be up to 20+ hr in anuria Hepatically metabolized (inactive), renally 90% renal eliminated Proarrhythmia, tachycardia, hypokalemia, Proarrhythmia, hypotension (avoid bolus), myocardial ischemia, tachyphylaxis (> 72 hr); tachycardia, < 1% thrombocytopenia, possible possible increased mortality with long-term use increased mortality with long-term use Consider in severe hypotension Consider if receiving a β-blocker or in those with high pulmonary artery pressures AC = adenylate cyclase; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; CO = cardiac output; PDE = phosphodiesterase; SVR = systemic vascular resistance. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-37 Acute Care in Cardiology I. Vasopressin Antagonists 1. Use is limited because of their significant cost and their limited effects on meaningful long-term ADHF outcomes. a. Should be viewed as “add on” therapy to aggressive diuresis and not as initial or adjunctive therapy for fluid removal b. Strict free water restriction is guideline recommended (expert opinion). 2. Tolvaptan is FDA approved for clinically significant hyponatremia associated with HF. a. In those at risk of or having active cognitive symptoms despite water restriction (i.e., serum sodium less than 125 mEq/L) b. In those with less marked hyponatremia (i.e., less than 135 mEq/L) having neurologic symptoms and who have no correction with fluid restriction, including patients with HF and syndrome of inappropriate secretion of antidiuretic hormone) 3. Clinical use: a. Oral dosing: 15 mg daily; then titrated to 30–60 mg as needed b. Pharmacology: Binds to and inhibits the V2 receptor, located in the renal tubule where water reabsorption is regulated i. Exerts its clinical effect within 2–4 hours and lasts about 24 hours ii. Increases serum sodium by about 2–4 mEq/L within 12–24 hours iii. Increases net urinary output and reduces total body weight (1–2 kg) c. Initiate only in the hospital setting to allow monitoring of volume status and serum sodium concentrations. d. An overly rapid rise in serum sodium can result in hypotension, hypovolemia, and neurologic sequelae. Maximum correction in 24 hours should be less than 8–10 mEq/L in those with chronic hyponatremia. e. Contraindicated with CYP3A4 inhibitors (tolvaptan is a substrate of 3A4) and in those with an eCrCl less than 10 mL/minute f. The FDA warns against use beyond 30 days (i.e., hepatotoxicity). g. Trials show effectiveness in correcting sodium with maintained therapy but no improvement in global clinical status or mortality and no reductions in rehospitalization. i. Role in long-term management of HF remains unclear. ii. Hyponatremia redevelops after therapy cessation. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-38 Acute Care in Cardiology III. ACUTE LIFE-THREATENING ARRHYTHMIAS A. Adult Cardiac Arrest (Figure 3) Start CPR (give oxygen; a�ach monitor/defibrillator) Rhythm shockable? YES (pulseless VT or VF) NO (asystole/PEA) Defibrilla�on (shock 1) CPR 2 min Establish IV/IO accessa Epinephrine 1mg IV/IO every 3–5 min Consider advanced airway, capnography CPR 2 min (establish IV/IO a access) Rhythm shockable? If ROSC, ini�ate post arrest care YES (pulseless VT or VF) NO Defibrilla�on (shock 2) CPR 2 min Epinephrine IV/IO Q 3–5 min (consider advanced airway, capnography) Rhythm Shockable? YES (pulseless VT or VF) NO Defibrilla�on (shock 3) CPR 2 min IV/IO amiodaroneb or lidocaineb Iden�fy and treat reversible causesc Figure 3. Adult Cardiac Arrest Algorithms If no IV/IO access, endotracheal administration of epinephrine, lidocaine, and atropine is allowed at 2–2.5 times the recommended IV/IO dose. Dilute this dose with 5–10 mL of sterile water or normal saline. b Amiodarone dosing is 300 mg IV/IO ×1; may repeat with 150 mg bolus ×1. If amiodarone is unavailable, lidocaine may be considered. Lidocaine 1–1.5 mg/kg IV, repeat 0.5–0.75 mg/kg IV/IO every 5–10 min (maximum 3 mg/kg). Lidocaine has not been shown to improve ROSC and hospital admission compared with amiodarone. c Hypovolemia, hypoxia, hydrogen ion (acidosis), hypokalemia or hyperkalemia, hypothermia, tension pneumothorax, tamponade (cardiac), toxins, thrombosis (pulmonary), thrombosis (coronary). ACLS = advanced cardiac life support; CPR = cardiopulmonary resuscitation; IO = intraosseous(ly); IV = intravenous(ly); PEA = pulseless electrical activity; ROSC = return of spontaneous circulation; VF = ventricular fibrillation; VT = ventricular tachycardia. a ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-40 Acute Care in Cardiology B. Targeted Temperature Management (TTM) after cardiac arrest 1. Indicated in adult patients who are comatose in whom return of spontaneous circulation (ROSC) has been achieved after cardiac arrest a. Improves neurologic outcomes after ROSC b. Optimal benefit for those in whom cooling begins soon after arrest 2. Cooling process a. Goal temperature: 32°C–36°C based on current 2020 ACLS guideline; however, newer data from TTM and TTM2 trials indicate fever avoidance is also reasonable. b. Duration: At least 24 hours after achieving the goal temperature c. Slowly rewarmed at a typical rate of 0.3°C/hour until core body temperature is reached 3. Pharmacologic therapy during TTM a. Shivering i. Occurs when body temperature drops below 36°C and diminishes below 34°C ii. Shivering increases heat production by 600% and increases oxygen consumption and is not desirable. iii. Agents used to reduce shivering include meperidine, buspirone, clonidine, dexmedetomidine, and neuromuscular blocking agents. b. Sedation i. Required to minimize pain or anxiety ii. Agents used to provide sedation include the combination of fentanyl, midazolam, or propofol. c. Other adverse effects related to hypothermia i. Bradycardia – Lower heart rates are associated with improved outcomes; therefore, no aggressive correction is required. ii. Electrolyte abnormalities (a) Magnesium – Maintain serum magnesium concentrations at normal to high range. (b) Potassium – Hypokalemia is common during the hypothermic phase, whereas hyperkalemia occurs during rewarming; avoid aggressive supplementation during hypothermia. iii. Bleeding (a) Increased risk because of impaired platelet function, reduced number of platelets, impaired production of clotting enzymes, etc. (b) Monitor prothrombin time and aPTT once the temperature falls below 37°C. iv. Arrhythmias (a) If life-threatening arrhythmias occur during hypothermia, cooling should be discontinued. (b) Treatment of life-threatening arrhythmias should generally follow advanced cardiac life support (ACLS) principles. v. Hyperglycemia (a) Hypothermia decreases insulin sensitivity and insulin secretion from the pancreas. (b) Maintain blood glucose concentrations of 140–180 mg/dL during TTM. vi. Hypotension (a) Patients may require blood pressure support during TTM. Recent data from the BOX trial showed no difference in MAP goal of 63 mm Hg versus 77 mm Hg; however, some clinicians may use higher MAP goals greater than 80 mm Hg. (b) Choice of vasoactive agents depends on patient heart rate, SBP, and risk of arrhythmias. vii. Monitor for infection and hepatic impairment, and use adjunctive treatments as necessary. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-41 Acute Care in Cardiology C. Symptomatic Bradycardia 1. If unstable, atropine 1 mg every 3–5 minutes (maximum dose 3 mg). (Note: Unstable = hypotension, acutely altered mental status, signs of shock, ischemic chest discomfort, acute HF) 2. If atropine fails, transcutaneous pacing, dopamine 5–20 mcg/kg/minute, or epinephrine 2–10 mcg/minute 3. Isoproterenol is a β-agonist commonly used for bradyarrhythmias when pacemaker therapy is not available. It has a number of precautions for use, including coronary disease and is not currently recommended as part of the adult bradycardia algorithm. D. Symptomatic Tachycardia 1. If unstable, synchronized cardioversion 2. If stable, determine whether the QRS complex is narrow or wide. a. Narrow-complex tachycardia (QRS less than 120 milliseconds); usually atrial arrhythmias i. Regular ventricular rhythm: Supraventricular tachycardia (SVT) or sinus tachycardia likely (a) Vagal maneuvers or adenosine 6-mg intravenous push, followed by a 20-mL saline flush, then a 12-mg intravenous push (may repeat once) (1) Rapid push followed by elevation of arm to increase circulation (2) Larger doses may be needed in patients taking theophylline or caffeine. (3) Initial dose should be reduced to 3 mg in patients taking dipyridamole or carbamazepine and in patients after heart transplantation, and when the drug is being given by central access. (4)  Use adenosine cautiously in severe CAD. (5) Adenosine should not be given to patients with asthma. (6) Do not give adenosine for unstable or for irregular or polymorphic wide-complex tachycardias because it can cause degeneration to ventricular fibrillation (VF). (b) If vagal maneuvers or adenosine fails to convert paroxysmal SVT, calcium channel blockers (CCBs) or β-blockers can be used. ii. Irregular (narrow complex) ventricular rhythm: AF (or possibly atrial flutter) (a) General management should focus on control of the rapid ventricular rate. (1) Usually non-dihydropyridine CCBs (diltiazem, verapamil) or β-blockers; digoxin sometimes useful (2) Rate is acceptable if it is less than 110 beats/minute at rest in asymptomatic persistent AF. (b) If the patient is hemodynamically unstable, synchronized cardioversion is recommended. (c) Patients with AF for more than 48 hours are at high risk of cardioembolic events and should not be immediately cardioverted, if stable. (d)  Transesophageal echocardiography before cardioversion is an alternative strategy to ensure the absence of left atrial clot. (e) Risk of thromboembolic event surrounding cardioversion (both pharmacologic and electrical) is greatest within the first 10 days. (f) Cardioversion (1) If AF for up to 7 days, either elective direct current conversion or pharmacologic cardioversion (A) Flecainide, dofetilide, propafenone, ibutilide, or amiodarone (proven efficacy) (B) Digoxin and sotalol are not recommended. (2) If AF lasts greater than 7 days, administer either elective direct current conversion or pharmacologic cardioversion with dofetilide, amiodarone, or ibutilide (proven efficacy). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-42 Acute Care in Cardiology b. Wide-complex tachycardia (QRS greater than 120 milliseconds): Usually ventricular arrhythmias i. VT or unknown mechanism (a) Consider adenosine only if regular and monomorphic. (b) Intravenous procainamide, amiodarone (or sotalol); lidocaine second line (c) Avoid procainamide and sotalol if prolonged QTc. (d) Avoid procainamide in CHF (e) Consider synchronized cardioversion for those with hemodynamic or clinical instability (acutely altered mental state, signs of shock, ischemic chest discomfort, acute heart failure, or hypotension) ii. Wolff Parkinson White syndrome with afibrillation (a)  Avoid all AV nodal blocking agents, including beta-blockers, diltiazem, verapamid, digoxin, and antiarrhythmics with AV nodal blocking properties (sotalol, amiodarone, etc.). (b) Procainamide is drug of choice for initial therapy. iii. Definite SVT with aberrancy: Probably transiently slowed or converted by adenosine iv. Polymorphic (irregular) VT (a) Induced primarily when the QTc interval is greater than 500 milliseconds (torsades de pointes) and commonly associated with acute MI (b) If unstable, polymorphic (irregular) VT requires immediate defibrillation with the same strategy as VF. (c) If stable, intravenous magnesium 1- to 2-g intravenous bolus (maximum 16 g every 24 hours) may be given; however, this is supported only by observational studies in the setting of wide QRS. (d)  Withdrawal of QT-prolonging medications, correction of low magnesium or K+ concentrations (1) Class I and III antiarrhythmic drugs (AADs) (2) Assess for drug interactions by CYP3A4 (e.g., azole antifungals, erythromycin). (3) Assess for other QTc-prolonging drugs (e.g., haloperidol, ziprasidone, droperidol, promethazine, macrolide and quinolone antibiotics, tricyclic antidepressants, or drugs contraindicated with dofetilide such as sulfamethoxazole/trimethoprim or thiazides). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-43 Acute Care in Cardiology E. AAD Overview (Tables 19 and 20) Table 19. Vaughan-Williams AAD Classes Class/Ion Affected Agents Physiologic Effect Result on Electrophysiologic Parameters Clinical Utility Class I/Na channel blockers + Ia (intermediate) Disopyramide ↓ Conduction velocity; quinidine, procainamide ↑ refractory period ↑ QRS complex and ↑ QT interval Atrial and ventricular arrhythmias Ib (fast) Lidocaine, mexiletine, phenytoin ↓ Conduction velocity; ↓↑ refractory period ↓ QT interval Ventricular arrhythmias Ic (slow) Flecainide, propafenone ↓↓↓ Conduction velocity; Ø refractory period ↑ QRS complex Atrial and ventricular arrhythmias Class II β-Blockers Metoprolol, esmolol, atenolol ↓ Conduction velocity; ↑ refractory period ↓ HR and ↑ PR interval Atrial and ventricular arrhythmias Class III K+ channel blockers Amiodarone,a dronedarone,a sotalol,b dofetilide, ibutilide Ø Conduction velocity; ↑↑↑ refractory period ↑ QT interval Atrial and ventricular arrhythmias Class IV Ca2+ channel blockers Diltiazem, verapamil ↓ Conduction velocity; ↑ refractory period ↓ HR and ↑ PR interval Atrial and ventricular arrhythmias Amiodarone and dronedarone have Ib, II, and IV class activity in addition to class III actions. Sotalol has 50%/50% β-blocking properties/K+-blocking properties. AAD = antiarrhythmic drug; Ca2+ = calcium; HR = heart rate; Na+ = sodium. ↑ = increases; ↓ = decreases; Ø = no effect. a b Table 20. AAD Properties and Dosing (class I and III agents only) AEs, Contraindications, PK, and Drug Interactions Drug Dosing by Indication Class Ia: Na channel blockers + Quinidine (Quinidex, Quinaglute) AEs: Nausea, vomiting, and diarrhea (30%), “cinchonism” (CNS and GI symptoms, tinnitus), strong vagolytic and anticholinergic properties, TdP (first 72 hr), hypotension, GI upset PK: Half-life 5–9 hr Potent inhibitor of CYP2D6; substrate and inhibitor of CYP3A4 DIs: Warfarin, digoxin AF conversion: Avoid use because of GI AEs AF and VT maintenance: Sulfate: 200–400 mg PO every 6 hr Gluconate (CR): 324 mg PO every 8–12 hr Decrease dose by 25% if CrCl < 10 mL/min Procainamide (Pronestyl) AEs: Hypotension (IV use, 5%), TdP CI: LVEF < 40% PK: Active metabolite NAPA (class III effects) may accumulate in renal dysfunction AF conversion: 1 g IV for 30 min; then 2 mg/min (1-hr efficacy 51%) AF maintenance: No oral agent available VT conversion: 20 mg/min IV until 17 mg/kg, arrhythmia ceases, hypotension, or QRS widens > 50% VT maintenance: 1–4 mg/min Reduce dose in renal and liver dysfunction ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-44 Acute Care in Cardiology Table 20. AAD Properties and Dosing (class I and III agents only) (Cont’d) AEs, Contraindications, PK, and Drug Interactions Drug Dosing by Indication Class Ia: Na channel blockers + Disopyramide (Norpace, Norpace CR) AEs: Anticholinergic effects, TdP, ADHF (potent negative inotropic effect) CIs: Cardiogenic shock, congenital long QT syndrome, second- or third-degree AVB, glaucoma PK: Half-life 4–8 hr Substrate of CYP2D6 DI: May enhance the effect of β-blockers AF conversion: IR 200 mg (if < 50 kg) or 300 mg (if > 50 kg) PO every 6 hr AF maintenance: 400–800 mg/day in divided doses (recommended adult dose 600 mg/day given as IR 150 mg PO every 6 hr or as CR 300 mg PO every 12 hr) If < 50 kg, moderate renal dysfunction (CrCl > 40 mL/ min) or hepatic dysfunction, max 400 mg/day If severe renal dysfunction (IR only; avoid CR) CrCl 30–40 mL/min, 100 mg every 8 hr CrCl 15–30 mL/min, 100 mg every 12 hr CrCl < 15 mL/min, 100 mg every 24 hr VTs: Use has fallen out of favor because of the availability of newer agents with less toxicity Class Ib: Na+ channel blockers Pulseless VT/VF conversion or VT with a pulse: 1–1.5 mg/kg IVP; repeat 0.5–0.75 mg/kg every 3–5 min (max 3 mg/kg) (If LVEF < 40%, 0.5–0.75 mg/kg IVP) (Amiodarone DOC in pulseless VT/VF; lidocaine acceptable if amiodarone not available) VT maintenance: 1–4 mg/min Reduce maintenance infusion in liver disease Lidocaine (Xylocaine) AEs: CNS (perioral numbness, seizures, confusion, blurry vision, tinnitus) CI: Third-degree AVB PK: Reduce dose in those with HF, liver disease, low body weight, and renal dysfunction and in older adults DI: Amiodarone (increased lidocaine concentrations) Mexiletine (Mexitil) AEs: CNS (tremor, dizziness, ataxia, nystagmus) VT maintenance: 200–300 mg PO every 8 hr; max 1200 mg/day CI: Third-degree AVB Reduce dose by 25%–30% in hepatic impairment PK: Half-life 12–20 hr Substrate CYP2D6, CYP1A2 Inhibitor CYP1A2 Class Ic: Na+ channel blockers (Note: Avoid in patients with HF or after MI; increased risk of sudden death) Propafenonea (Rythmol, Rythmol SR) AEs: Metallic taste, dizziness, ADHF, bronchospasm, bradycardia, heart block (negative inotropy and β-blocking properties) CIs: HF (NYHA III–IV), liver disease, valvular disease (TdP), CAD, MI PK: Half-life 10–25 hr Substrate CYP2D6, CYP1A2, CYP3A4 Inhibitor CYP1A2, CYP2D6 DIs: Digoxin ↑ by 70%; warfarin ↑ by 50% as well as drugs that inhibit CYP 2D6, 1A2, 3A4 (increased propafenone) AF conversion: 600 mg PO × 1 (efficacy 45% at 3 hr) 450 mg PO × 1 (weight < 70 kg) AF maintenance: HCl: 150–300 mg PO every 8–12 hr HCl (SR): 225–425 mg PO every 12 hr Reduce dose 70%–80% in hepatic impairment Flecainidea (Tambocor) AEs: Dizziness, tremor, ADHF (negative inotropy), vagolytic, anticholinergic, hypotension CIs: HF, CAD, valvular disease, LVH (TdP) PK: Half-life 10–20 hr Substrate CYP2D6, CYP1A2 Inhibitor CYP2D6 DI: Digoxin ↑ by 25% AF conversion: 300 mg PO × 1 (efficacy 50% at 3 hr) AF maintenance: 50–150 mg PO BID Reduce dose by 50% when CrCl < 35 mL/min ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-45 Acute Care in Cardiology Table 20. AAD Properties and Dosing (class I and III agents only) (Cont’d) AEs, Contraindications, PK, and Drug Interactions Drug Dosing by Indication Class III: K channel blockers + Amiodarone (Cordarone) AEs: Pulmonary fibrosis 3%–17%, hyperthyroidism 3%, hypothyroidism 30%, neurologic toxicity 20%–40%, GI upset, photosensitivity, corneal deposits, hepatitis, blue-gray skin 15%, TdP < 1%, heart block 14%, hypotension (IV), phlebitis (IV; Ca2+and β-blocking properties), bradycardia CIs: Iodine hypersensitivity, hyperthyroidism, third-degree AV heart block PK: Half-life 58 days (avg) Inhibits CYP3A4/2D6/2C9/1A2/2C19 and intestinal P-gp Substrate CYP3A4/1A2/2C19/2D6 DIs: Warfarin, digoxin, statins (max simvastatin dose 20 mg/day), phenytoin ↑ ≥ 50%, lidocaine, and others Does not increase mortality in patients with HF AF conversion: IV: 5–7 mg/kg IV over 30–60 min, then 1.2–1.8 g/day continuous IV or divided oral doses until 10 g PO: 1.2–1.8 g/day in divided doses until 10 g AF maintenance: 200–400 mg/day PO Pulseless VT/VF conversion: 300 mg or 5 mg/kg IVB in 20 mL of D5W or NS; repeat 150 mg IVB every 3–5 min Stable VT: 150 mg IVB in 100 mL of D5W for 10 min VT/VF maintenance: 1 mg/min × 6 hr, then 0.5 mg/min (max 2.2 g/day) Sotalol AEs: ADHF, bradycardia, AVB, wheezing, 3%–8% (Betapace, Betapace AF) TdP within 3 days of initiation, bronchospasm (β-blocking effects) CIs: Baseline QTc > 440 ms or CrCl < 40 mL/ min (AF only), LVEF < 40% PK: Renally eliminated, half-life 30–40 hr Hospitalization ideal for initiation of therapy because of BW: Do not initiate if baseline QTc interval > 450 ms; if QTc > 500 ms during therapy, reduce the dose, prolong the infusion duration, or d/c use Not effective for AF conversion AF maintenance (based on CrCl): 80 mg PO BID (> 60 mL/min) 80 mg PO daily (40–60 mL/min) CI < 40 mL/min VT maintenance (based on CrCl): 80 mg PO BID (> 60 mL/min) 80 mg PO daily (30–60 mL/min) 80 mg PO every 36–48 hr (10–30 mL/min) 80 mg PO: Individualize; every 48 hr minimum (< 10 mL/min) IV dosing depends on target oral dose and creatinine clearance. Dofetilide (Tikosyn) AF conversion (based on CrCl calculated with actual body weight; efficacy 12% at 1 mo): 500 mcg PO BID (> 60 mL/min) 250 mcg PO BID (40–60 mL/min) 125 mcg PO BID (20–39 mL/min) CI < 20 mL/min AF maintenance: Dose as above according to renal function; adjust for QTc NTE 500 ms or > 15% ↑ in QTc AEs: TdP (0.8%; 4% if no renal adjustment), diarrhea CIs: Baseline QTc > 440 ms or CrCl < 20 mL/ min or, CI in patients with intraventricular conduction delays with baseline QT > 500 msec; NTE 550 msec PK: Renal and hepatic elimination Half-life 6–10 hr Substrate CYP3A4 DIs: CYP3A4 inhibitors and drugs secreted by kidney (cimetidine, ketoconazole, verapamil, trimethoprim, prochlorperazine, dolutegravir, megestrol), HCTZ BW: Hospitalization mandatory for initiation, obtain QTc 2–3 hr after each of the first five doses, reduce 50% if QTc ↑ > 15%; NTE QTc > 500 ms Does not increase mortality in patients with HF ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-46 Acute Care in Cardiology Table 20. AAD Properties and Dosing (class I and III agents only) (Cont’d) AEs, Contraindications, PK, and Drug Interactions Drug Dosing by Indication Class III: K channel blockers + Ibutilide (Corvert) AEs: TdP 8%, AV heart block (β-blocking properties) CIs: Baseline QTc > 440 ms, LVEF < 30%, concomitant AADs PK: Half-life 2–12 hr (avg 6) DIs: CYP3A4 inhibitors or QT-prolonging drugs ECG monitoring during and 4 hr after DCC AF conversion: 1 mg IV (≥ 60 kg) or 0.01 mg/kg IV (< 60 kg); repeat in 10 min if ineffective (efficacy 47% at 90 min) BW: Potentially fatal arrhythmias (e.g., polymorphic VT) can occur with ibutilide, usually in association with TdP; patients with chronic AF may not be the best candidates for ibutilide conversion Dronedarone (Multaq) AEs: Worsening HF, QT prolongation, hypokalemia or hypomagnesemia with K+-sparing diuretics, hepatic failure CIs: QTc ≥ 500 ms or PR ≥ 280 ms, NYHA class IV HF or NYHA class II–III HF with recent ADHF, severe hepatic impairment, second- or third-degree AVB, or HR < 50 beats/min PK: Half-life 13–19 hr Substrate 3A4 Inhibitor intestinal P-gp DIs: CYP3A4 inhibitors, QT-prolonging drugs, simvastatin, tacrolimus/sirolimus, warfarin, and other