The Cleveland Clinic Cardiology Board Review, 2ed.

Cardiovascular Medicine—Essential Pharmaceuticals

Katherine M. Greenlee and Michael A. Militello

Cardiovascular disease (CVD) accounts for nearly 50% of all death in Western societies and 25% of all death worldwide. Furthermore, cardiac medications rank second in frequency of use worldwide, after antibiotics. Medical therapy plays an essential role, not only in the management of CVD but also in prevention.

Pharmacology accounts for about 12% of the questions on the Cardiology Boards. The topic is vast and may be approached in various ways. Pharmacokinetics and dynamics, drug interactions, and antiarrhythmics are addressed in other chapters. In this chapter, we cover most of the available cardiovascular drugs used in clinical practice in the United States. We review names (brand and generic), starting and maximum doses, mechanisms of action, labeled and unlabeled indications, and side effects. When appropriate, we comment on the major clinical trials involving the particular drug. The classes and drugs are classified alphabetically according to mechanistic class and/or therapeutic class, as shown in Table 61.1.

TABLE

61.1 Major Classes of Cardiac Medications, Listed Alphabetically

^aAntiarrhythmics are covered in Chapter 10.

ADRENERGIC AGONISTS

Before detailing specific medications, we review basic information on adrenergic receptors that is useful for understanding the mechanism and side effects of this class as well as classes discussed subsequently. The adrenoceptors are classified into alpha (α) and beta (β) subtypes. There are two main subtypes of α-adrenoceptors, α₁ and α₂, and three main types of β-adrenoceptors, β₁, β₂, and β₃. The primary effects of receptor activation are shown in Table 61.2. The adrenergic agonists of cardiac interest in this section are the α₂ agonists, which act centrally. In later sections, we discuss other adrenergic agonists that stimulate α and β receptors, such as epinephrine, norepinephrine, dobutamine, and other inotropes and pressors.

TABLE

61.2 Main Effects of Receptor Activation of Adrenoceptors

The α₂ Agonists (Clonidine, Guanabenz, Guanfacine)

Mechanism of Action

The α₂ receptors are presynaptic and are found in the central nervous system (CNS). Stimulation of the a₂ receptors decreases sympathetic outflow from the CNS, thus lowering blood pressure and, in some patients, heart rate.

Side Effects

Common side effects include sedation, dry mouth, hypotension, dizziness, sexual dysfunction, bradycardia, nausea, headache, and depression. Abrupt withdrawal of therapy causes rebound hypertension. Rebound hypertension can be severe with concurrent administration of beta-blockers secondary to unopposed α₁-receptor stimulation.

Indication and Precautions

Clonidine (Catapres and Catapres-TTS) Clonidine is labeled for use in hypertension. For patients with severe renal insufficiency (i.e., CrCl <10 mL/min), doses should be reduced by 25% to 50%. Transdermal patches are replaced weekly.

Methyldopa (Aldomet) (Oral); Methyldopate HCL (Intravenous) Methyldopa is labeled for use in hypertension and hypertensive emergency (IV only) and is one of the few drugs that can be used for hypertension in pregnant women. In addition to the general side effects of α₂-receptor agonists, methyldopa has specific side effects: peripheral edema, hemolytic anemia, drug fever, systemic lupus erythematosus (SLE)-like syndrome, nightmares, hepatocellular injury, hepatitis (rare), and anxiety. Positive Coombs tests occur within 6 to 12 months in 10% to 20% of patients.

ADRENERGIC ANTAGONISTS

This section is divided according to the various subgroups of adrenergic antagonists, based on the adrenergic receptors they block, and include α₁-receptor antagonists, β-receptor antagonists, and nonselective α/β antagonists.

α₁-Receptor Antagonists

Selective α₁, Antagonists: Doxazosin (Cardura), Prazosin (Minipress), Terazosin (Hytrin)

Mechanism of Action Selective α₁-receptor antagonists act peripherally and lead to arterial and venous vasodilation.

Side Effects Side effects of α₁-receptor antagonists include orthostatic hypotension, dizziness, light-headedness, drowsiness, headache, dry mouth, and malaise. The first dose should be given at bedtime to limit effects associated with orthostatic hypotension. Tachyphylaxis may develop with long-term administration in patients with heart failure (e.g., prazosin).

Indications and Precautions These drugs are labeled for use in hypertension and benign prostatic hypertrophy (BPH) (terazosin and doxazosin).

Major Clinical Trials

VHeFT I.¹ In this trial, hydralazine combined with nitrates and prazosin was compared to placebo for the treatment of heart failure. No effect on the primary endpoint of mortality was observed, and no difference in left ventricular (LV) ejection fraction was observed when prazosin was compared to placebo.

ALLHAT.² This trial was designed to evaluate different antihypertensive medications to reduce cardiovascular events. An interim analysis 2 years before the final publication demonstrated that patients receiving doxazosin had a significantly higher rate of stroke cardiovascular events, and the rate of congestive heart failure (CHF) was two times higher. The doxazosin arm was stopped early as a result of the findings.

Nonselective α Antagonists: Phentolamine (Regitine)

Mechanism of Action Nonselective α-adrenergic antagonist with similar affinities for α₁ and α₂ receptors, producing vasodilation and an increase in heart rate

Side Effects Side effects of these drugs include hypotension, tachycardia, arrhythmias, angina, and nausea/vomiting/diarrhea. They may exacerbate peptic ulcer disease (PUD) and produce nasal congestion.

Indications and Precautions Phentolamine is labeled for use in hypertensive crisis in patients with pheochromocytoma and for treatment of skin necrosis in patients with norepinephrine, dopamine, epinephrine, and phenylephrine extravasation.

β-Receptor Antagonists

Beta-blockers were first discovered in 1958 (dichloroiso-prenaline). The effects produced depend on the degree of endogenous sympathetic activity and are less dramatic at rest. Beta-blockers are classified as selective and nonselective as well as having α₁-blocking properties.

Mechanism of Action Nonselective beta-blockers antagonize both β₁ and β₂ receptors, inhibiting the effects of catecholamines on these receptors. Cardiovascular effects include decreases in contractility and heart rate. Noncardiovascular effects mediated through β₂ blockade include increased peripheral vascular resistance or bronchospasm. Selective beta-blockers antagonize β₁ receptors to a greater extent than β₂receptors, when administered in typical or usual doses. Cardiovascular effects are the same as with nonselective beta-blockers. Both classes generally lead to a decrease in blood pressure, sinus node automaticity, conduction through the atrioventricular (AV) node, and increased AV nodal refractoriness. The antiarrhythmic properties are a class effect. Other pharmacologic properties of selective beta-blockers include intrinsic sympathomimetic activity (ISA). Agents that have ISA are partial βagonists during low catecholamine states, preventing resting bradycardia; however, they act as full agonists when endogenous catecholamine levels increase. Beta-blockers without ISA activity have been shown to decrease recurrent myocardial infarction (MI), sudden death, and overall mortality in acute-MI survivors. They also have been shown to reduce mortality and hospitalizations secondary to heart failure. A new beta-blocker, nebivolol, is a selective β₁antagonist that also reduces systemic vascular resistance (SVR) by producing an endothelium-derived nitric oxide (NO)-dependent vasodilation. A list of the various beta-blockers that are used is provided in Table 61.3.

TABLE

61.3 Pharmacokinetics of Commonly Used Beta-Blockers

^aEsmolol is an IV-formulated drug. The loading dose is 500 µg/kg given over 1 min. Then, the maintenance dose is 25–300 µg/kg/min.

^bMetoprolol is available as an immediate-release preparation and as an extended-release preparation. The extended-release product is labeled for both hypertension and heart failure.

ISA, intrinsic sympathomimetic activity.

Side Effects Side effects of these drugs include fatigue, bradycardia, heart block, bronchospasm, depression, lipid abnormalities, masking the symptoms of hypoglycemia, a rebound effect with abrupt discontinuation, precipitation of heart failure, and impotence.

Indications and Precautions Indications for beta-blockers include hypertension, ischemic heart disease, acute myocardial infarction (AMI), stable and unstable angina (UA), heart failure, arrhythmia, and stable heart failure (see Table 61.3). Absolute contraindications include hypersensitivity to beta-blockers, asthma, heart block greater than first degree, insulin-dependent diabetics with frequent hypoglycemic episodes, and overt heart failure. Relative contraindications include chronic obstructive lung disease, diabetes mellitus, and severe peripheral arterial disease. Beta-blockers have significant interactions with other drugs, including medications that slow AV nodal conduction such as digoxin, diltiazem, and verapamil, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), other antihypertensive medications, other negative inotropic agents, rifampin, phenobarbital, phenytoin, cholestyramine, and colestipol, to name a few.

Combined α-/β-Receptor Antagonists

Mechanism of Action The combination preparations are specific α₁-receptor antagonists, but nonselective b-receptor antagonists. Labetalol is 7:1 selective b to a receptor in the IV preparation and 3:1 in the oral preparation.

Side Effects Refer to side effects of beta-blockers.

Indications and Precautions The labeled indication of labetalol is hypertension. Carvedilol has labeled indications for hypertension, as well as LV dysfunction following MI (clinically stable patients), and mild to severe chronic heart failure. Refer to precautions for beta-blockers.

Major Clinical Trials

MERIT-HF.³ Metoprolol CR/XL improved survival and New York Heart Association (NYHA) functional class and reduced the number of hospitalizations and days in the hospital due to worsening heart failure.

CIBIS-II.⁴ This trial demonstrated that bisoprolol therapy was well tolerated and reduced mortality and hospitalization rates in patients with stable CHF.

CAPRICORN.⁵ This trial showed that long-term therapy with carvedilol, in addition to angiotensin-converting enzyme inhibitor (ACE-I) and standard therapy, reduced mortality and recurrent MI in stable patients with LV systolic dysfunction after acute MI.

COPERNICUS.⁶ This trial studied the effect of carvedilol on survival in patients with severe chronic heart failure. Carvedilol reduced mortality in patients with severe CHF by 34% and also reduced the number of days spent in hospital because of CHF and for any cause.

COMET.⁷ Carvedilol improved survival and LV ejection fraction to a greater degree than immediate-release metoprolol during long-term therapy for heart failure.

BHAT.^8,9 The Beta-blocker Heart Attack Trial, using propanolol, and the Norwegian Multicenter Study Group, using timolol, both showed a reduction in mortality rate, reinfarction rate, or both with the use of the beta-blocker.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

The renin–angiotensin system (RAS) is a hormonal system that interacts very closely with the sympathetic nervous system, angiotensin II formation, and aldosterone secretion. It has an essential role in sodium and volume management. Renin, an enzyme, is secreted by the juxtaglomerular apparatus located in the wall of the arteriole of the glomerulus. It is secreted secondary to multiple stimuli, low sodium concentration of the fluid in the distal tubule, stimulation of the β-adrenoceptors, and circulating prostacyclin and NO, as shown in Figure 61.1.

FIGURE 61.1 The renin–angiotensin–aldosterone pathway and mechanism of action of ACE-I and ARBs. ACE is a membranebound enzyme on the surface of endothelial cells abundant in the lung (+ve, positive or stimulatory effect; –ve, negative or inhibitory effect).

The RAS pathway is important in the pathogenesis of heart failure and hypertension; hence all aspects of this pathway are targets for therapy in CHF and hypertension, whether in renin release such as beta-blockers, angiotensin II formation such as ACE-I, or angiotensin II blockade such as angiotensin II receptor blockers (ARBs) and aldosterone antagonists.

Mechanism of Action

ACE-I block the conversion of angiotensin I to angiotensin II by inhibiting ACE, as shown in Figure 61.1. In response to this blockade, there is decreased formation of angiotensin II, leading to vasodilatation. Also, there is a decrease in the breakdown of bradykinins, which may produce additional vasodilatory effects.

Side Effects

Side effects include cough (because of decrease in breakdown of bradykinin), acute renal failure (particularly if there is bilateral renal artery stenosis), angioedema, hyperkalemia, proteinuria, hypotension (which needs to be monitored after the first dose and in water-depleted patients), headache, rash, neutropenia/agranulocytosis, and dizziness.

Angioedema is rare but may occur at any time; when it does occur, however, it is usually early in therapy. Severe hypotension may be seen in volume-depleted patients; hence the volume status of a heart failure patient should be carefully assessed before initiating therapy. Neutropenia or agranulocytosis has been reported with many ACE-I and is usually associated with collagen vascular disorders, higher doses, and renal dysfunction.

Indications and Precautions

ACE-I are labeled for use in hypertension, heart failure, LV dysfunction, post-AMI, and diabetic nephropathy (Table 61.4). ACE-I are contraindicated in pregnancy and in patients with bilateral renal artery stenosis or unilateral renal artery stenosis in patients with a solitary kidney.

TABLE

61.4 Preparations and Dosing of Available ACE-I

Major Clinical Trials

SAVE.^10,11 The SAVE trial showed that the long-term use of captopril in patients with asymptomatic LV dysfunction following acute MI was associated with lower mortality and morbidity.

GISSI-3.¹² This trial showed that lisinopril therapy reduced mortality and improved outcome after MI. The mortality benefit manifested primarily during the early phase (6 weeks), whereas the LV remodeling benefit manifested later.

TRACE.¹³ The TRACE trial update confirmed that trandolapril reduced death and major cardiovascular complications in diabetic patients after infarction.

HEART.¹⁴ The HEART trial showed that in patients with acute anterior MI, early use of ramipril (titrated to 10 mg) attenuated LV remodeling and resulted in swift LV recovery.

AIREX.¹⁵ This trial showed that beneficial effects of ramipril started early after MI in patients with heart failure, and that the benefit was sustained over several years.

CONSENSUS.¹⁶ CONSENSUS studied the effects of enalapril on mortality in severe CHF. Enalapril reduced mortality and improved symptoms in severe CHF, when added to conventional therapy.

V-HeFT II.¹⁷ This trial compared enalapril with hydralazine–isosorbide (H-ISDN) for the treatment of CHF. Mortality with enalapril was significantly lower than in the H-ISDN group.

Stop-Hypertension-2.¹⁸ This trial showed that ACE-I and calcium channel blockers have similar efficacy in prevention of cardiovascular mortality compared to older-generation antihypertensive drugs (diuretics and beta-blockers) in elderly patients. ACE-I was associated with less MI and CHF than calcium channel blockers, but not compared to conventional therapy with diuretics and beta-blockers.

ANGIOTENSIN-II RECEPTOR BLOCKERS

Mechanism of Action

ARBs block angiotensin II (A-II) from binding to angiotensin II type 1 receptors (AT₁), thereby inhibiting the vasoconstrictor and aldosterone-secreting effects of angiotensin II (see Fig. 61.1; Table 61.5). ARBs do not alter the metabolism of bradykinin or neuropeptides, so they should not cause side effects related to this effect, such as cough. However, there are case reports of angioedema occurring with ARB therapy.

TABLE

61.5 Formulations of ARBs

Side Effects

Side effects include hypotension, acute renal failure (particularly if there is bilateral renal artery stenosis), hyperkalemia, proteinuria, hypotension, dizziness, headache, and angioedema (rare).

Indications and Precautions

The labeled use for all ARBs is hypertension; however, both candesartan and valsartan are also labeled for heart failure. Candesartan is labeled for cardiovascular mortality reduction for patients with reduced LV dysfunction post-MI. Losartan is also labeled for hypertension in patients with LV hypertrophy, as well as prophylaxis of diabetic nephropathy in patients with a history of hypertension. Additionally, irbesartan also carries an indication for prophylaxis against diabetic nephropathy in patients with a history of hypertension.

Major Clinical Trials

ELITE-II.¹⁹ This trial demonstrated that losartan was not superior to captopril in reducing mortality in patients with CHF who were >60 years of age.

CHARM.²⁰ This trial had multiple arms. The CHARM-alternative looked at candesartan in patients with symptomatic heart failure who were intolerant of ACE-I. Patients were randomized to either candesartan or placebo. There was decreased risk of cardiovascular death or hospitalization from heart failure in the candesartan group compared to the placebo group. The CHARM-added trial randomized patients with symptomatic heart failure who were already on ACE-I to either candesartan or placebo. In contrast to the results of Val-HeFT, mortality was significantly reduced by addition of an ARB to an ACE-I compared to the ACE-I alone. The CHARM-preserved arm of the study looked at patients with symptomatic heart failure with preserved ejection fraction. They were randomized to either candesartan or placebo. There was no difference in the primary endpoint (cardiovascular death or hospitalization secondary to CHF).

LIFE.²¹ This trial showed that losartan was more effective than atenolol in preventing death, cardiovascular accidents (CVA), and MI as a combined endpoint. In terms of single outcomes, the reduction in CVA was significant, whereas the reduction in death or MI was only a trend without statistical significance.

Val-HeFT.²² This trial showed that valsartan reduced the combined endpoint of death and morbidity and improved symptoms and signs of CHF. The benefit was seen only in patients who were not receiving ACE-I. In patients who were on ACE-I and beta-blockers, the addition of valsartan was associated with increased mortality.

RESOLVD.²³ This trial showed that both candesartan and enalapril were effective, safe, and tolerated in the treatment of CHF. Combination of candesartan and enalapril reduced LV dilatation greater than either agent alone.

RENAAL.²⁴ This trial showed that losartan preserved renal function in patients with type II diabetes and diabetic nephropathy, as well as decreasing hospitalization for CHF.

ALDOSTERONE RECEPTOR ANTAGONISTS

Mechanism of Action

As shown in Figure 61.1, this class of drugs antagonizes aldosterone at the mineralocorticoid receptor, consequently inhibiting aldosterone effects in the late distal convoluted tubule and cortical collecting duct, reducing sodium reuptake (hence the diuretic effect) and reducing potassium excretion (hence the side effect of hyperkalemia).

Side Effects

Side effects of spironolactone include hyperkalemia, hypotension, fatigue, rash, gynecomastia, amenorrhea, breast tenderness, sexual dysfunction, headache, nausea/vomiting, and diarrhea. With eplerenone, hyperkalemia is the predominant effect, with gynecomastia much less common. Drug–drug interactions are common with eplerenone, especially when concomitant medications increase serum potassium levels and when it is given with potent inhibitors of the CYP 3A4 isoenzyme system.

Indications and Precautions

Spironolactone is labeled for primary aldosteronism, edema, hypertension, severe heart failure (NYHA Class III-IV) to increase survival and reduce hospitalization when added to standard therapy, and hypokalemia associated with loop diuretics. Use at a dose of 25 mg daily as an adjunct therapy for patients with Class III to IV CHF. Eplerenone is labeled for use in hypertension and for treatment in patients with LV dysfunction after MI. It is important to point out that this class of drugs should be avoided in patients with renal dysfunction (creatinine >2.5 mg/dL) or hyperkalemia.

Major Clinical Trials

RALES.²⁵ RALES found that the addition of spironolactone to standard-therapy ACE-I, loop diuretic, and digoxin reduced mortality and hospitalizations due to heart failure, with a 30% decrease in mortality in patients with NYHA Class III or IV heart failure.

EPHESUS.²⁶ This trial was designed to assess the safety and efficacy of eplerenone in patients with CHF after acute MI. The study showed a 15% decrease in mortality in patients with CHF post-MI.

EMPHASIS-HF.²⁷ This trial added eplerenone (up to 50 mg daily) or placebo to recommended therapy in patients with NYHA functional Class II heart failure and an ejection fraction of no more than 35%. Primary outcome was the composite of death from cardiovascular causes or first hospitalization for heart failure. For patients in the eplerenone group, primary outcome occurred in 249 patients (18.3%) and in 356 patients (25.9%) in the placebo group with a hazard ratio for primary outcome for eplerenone compared to placebo of 0.63 (95% confidence interval, 0.54 to 0.74; p < 0.001). Of note, serum potassium levels above 5.5 mmol/L occurred in 158 patients (11.8%) in eplerenone group compared to 96 patients (7.2%) in the placebo group, (p <0.001).

RENIN INHIBITORS

Mechanism of Action

Aliskiren is a direct renin inhibitor blocking the conversion of angiotensinogen to angiotensin I, which, in turn, decreases formation of angiotensin II.

Side Effects

Side effects include increased BUN and serum creatinine, hyperkalemia, hypotension, and angioedema.

Indications and Precautions

The labeled indication for aliskiren is for hypertension. This medication has not been studied in patients with severe renal impairment. It is recommend to avoid use in patients with worsening renal function, or renal artery stenosis (bilateral or unilateral).

ANTICOAGULANTS

Anticoagulant drugs are subclassified into unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), direct thrombin inhibitors, and oral anticoagulants. A diagram of the coagulation cascade is shown in Figure 61.2.

FIGURE 61.2 The blood coagulation pathways, intrinsic and extrinsic, and the sites of impact of anticoagulant. When the arrow is not marked, it indicates either a positive effect of a factor on a step in the pathway or a transformation into another factor. The negative effect is marked on the relevant arrows (+ve, positive or stimulatory effect; –ve, negative or inhibitory effect).

Unfractionated Heparin

Mechanism of Action

UFH is a thrombin inhibitor that binds to antithrombin, increasing antithrombin’s activity to inactivate thrombin in addition to activated factors IX, X, XI, and XII.

Side Effects

Common side effects include bleeding, thrombocytopenia (benign type I and more severe type II, which may cause thrombosis), elevation in aspartate aminotransferase (AST)/alanine aminotransferase (ALT), osteoporosis (long-term therapy), and hyperkalemia.

Indications and Precautions

Heparin is administered subcutaneously or as an IV preparation. Generally, a weight-based nomogram is utilized that is titrated to a specific activated partial thromboplastin (aPTT) level. It is labeled for use in the treatment and prophylaxis of venous and arterial thrombosis. Heparin-induced thrombocytopenia (HIT) occurs in two forms, type I (non–antibody-mediated reaction) and type II (antibody-mediated reaction—typically IgG). Thromboembolic complications (e.g., deep vein thrombosis [DVT], MI, stroke) are associated with type II HIT and can be life-threatening. The incidence of thrombocytopenia is 10% to 15%, but the incidence of developing type II HIT is around 1% to 3%.

FACTOR XA INHIBITORS

Fondaparinux (Arixtra)

Mechanism of Action

Fondaparinux inhibits activated factor Xa through the neutralization capacity of antithrombin III.

Side Effects

Common side effects include bleeding, injection site–related bleeding, rash, and pruritus. Asymptomatic increases in AST and ALT may occur.

Indications and Precautions

Fondaparinux is used for prophylaxis of DVT in patients undergoing orthopedic or abdominal surgery. It is also indicated for treatment of acute pulmonary embolism (PE) and acute DVT (with or without PE). Fondaparinux is contraindicated in patients with a creatinine clearance <30 mL/min and in patients weighing <50 kg. As with direct thrombin inhibitors, there is no known antidote for fondaparinux.

Rivaroxaban (Xarelto)

Mechanism of Action

This prevents clot formation by selective inhibition of factor Xa.

Side Effects

Common side effects include bleeding (6%), ALT or AST elevation greater than three times upper limit of normal (3%).

Indications and Precautions

Rivaroxaban is indicated for thromboprophylaxis post knee or hip replacement. Avoid use in patients with moderate to severe hepatic dysfunction or severe (CrCl<30 mg/dL) renal dysfunction.

Major Clinical Trials

OASIS-5.²⁸ This trial compared efficacy and safety of fondaparinux to enoxaparin in patients with UA or non–ST-elevation myocardial infarction (NSTEMI).

The primary efficacy endpoint composite of death, MI, and refractory ischemia at 9 days validated noninferiority of fondaparinux (5.8%) compared with 5.7% for enoxaparin (HR 1.01; 95% CI 0.90 to 1.13; p = 0.007). The safety endpoint of major bleeding at 9 days was reduced with fondaparinux (2.2%) compared to 4.1% with enoxaparin (HR 0.52; 95% CI 0.44 to 0.61; p < 0.001). Of note, major bleeding in patients with CrCl < 30 mL/min was less with fondaparinux (2.4%) compared to 9.9% with enoxaparin (p = 0.001). Patients in whom percutaneous coronary intervention (PCI) was performed who received enoxaparin 6 or more hours before the procedure were administered UFH during the procedure, which may lead to a higher risk of bleeding. Of concern was the rate of guiding-catheter thrombus formations that occurred in the fondaparinux group (29 episodes [0.9%] vs. 8 episodes [0.3%]).

OASIS-6.²⁹ This study evaluated efficacy of fondaparinux with UFH in patients with acute ST-elevation myocardial infarction (STEMI). This was a randomized, double blind trial. There were two treatment groups, stratum 1, in which patients had no indication to receive UFH, and stratum 2, in which patients had an indication for UFH such as use of fibrinolytic therapy, patients not eligible for fibrinolysis but eligible for UFH, or primary PCI patients. Stratum 1 patients received fondaparinux for up to 8 days. Stratum 2 received either fondaparinux or placebo, with a control group receiving UFH for 24 to 48 hours. The primary endpoint at 30 days of death or reinfarction for fondaparinux was 9.7% compared to UFH or placebo group, which was 11.2% leading to a 14% risk reduction (0.86 HR; 95% CI, 0.77 to 0.96, p = 0.008). No difference was found between fondaparinux (2.1%) and the UFH or placebo group (1.8%) (0.83 HR; 95% CI, 0.64 to 1.06, p = 0.14) for major bleeding. For fondaparinux compared to control, significant benefit was found for patients without reperfusion (15.1% control, 12.2% fondaparinux, HR, 0.80; 95% CI, 0.65 to 0.98; p = 0.003), with fibrinolytic (13.6% vs. 10.9%; HR, 0.79; 95% CI, 0.68 to 0.92; p = 0.003), but not for the primary PCI patients (4.9% vs. 6.0%; HR, 1.24; 95% CI, 0.95 to 1.63; p = 0.12). With regard to PCI, as seen in OASIS-5, there was a significant rate of guiding-catheter thrombosis with fondaparinux (22 vs. 0; p < 0.001).

ROCKET AF.³⁰ Rivaroxaban was compared to warfarin in patients with nonvalvular atrial fibrillation at moderate to high risk for stroke. Elevated risk was signified by history of stroke, transient ischemic attack, or systemic embolism, or at least two of the following: heart failure or ejection fraction of 35% or less, hypertension, age 75 or more, or diabetes mellitus. The composite of stroke (ischemic or hemorrhagic) and systemic embolism was the primary endpoint. This occurred in the rivaroxaban group (1.7% per year) versus in the warfarin group (2.3% per year) (HR for rivaroxaban group, 0.79; 95% CI, 0.66 to 0.96; p <0.001 for non-inferiority). Major bleeding was similar between the groups (3.6% and 3.4%, p = 0.58). Rates of intracranial hemorrhage were lower in the rivaroxaban group (0.5% vs. 0.7% per year; HR, 0.67; 95% CI, 0.47 to 0.93). Major bleeding from a gastrointestinal site was significantly higher for rivaroxaban (3.2% vs. 2.2, p < 0.001). Of note, patients in the warfarin group were in therapeutic range for INR 55% of the time, which is lower than previous studies (range, 64% to 68%).

Direct Thrombin Inhibitors: Bivalirudin (Angiomax), Lepirudin (Refludan), Argatroban (Argatroban), Dabigatran (Pradaxa)

Mechanism of Action

These drugs bind directly to thrombin (factor IIa), causing it to be inactivated (see Fig. 61.2). Bivalirudin, dabigatran, and argatroban bind directly and reversibly, whereas lepirudin binds directly and irreversibly.

Side Effects

Common side effects include bleeding. Patients on lepirudin may develop antibodies against lepirudin that decrease the elimination of lepirudin, hence increasing the duration of activity. Recent data demonstrated that patients may develop anaphylactic reactions with administration of lepirudin, and the occurrence is higher in patients who have previously been treated with the drug. Dabigatran has an increased incidence of dyspepsia (11%), but absorption of dabigatran is decreased by 20% to 25% when given in combination with proton pump inhibitors.

Indications and Precautions

Bivalirudin, lepirudin, and argatroban are given intravenously, and dabigatran is available orally. They are listed in Table 61.6. The labeled indication for bivalirudin is for percutaneous transluminal coronary angioplasty (PTCA) in the setting of UA. Dabigatran is indicated for prevention of stroke and systemic embolization in nonvalvular atrial fibrillation. There are no reversal agents for the direct thrombin inhibitors.

TABLE

61.6 Preparations, Dosing, and Indications for Direct Thrombin Inhibitors

^aHalf-life depends on renal function.

aPTT, activated partial thromboplastin; PT, prothrombin time; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention; ACT, activated clotting time; PTCA, percutaneous transluminal coronary angioplasty.

Major Clinical Trials

Thrombin Inhibitors Trialist (DTIT) Collaborative Group.³¹ This meta-analysis reviewed the use of direct thrombin inhibitors in acute coronary syndrome (ACS). A total of 5,674 patients were included, of whom 4,603 underwent PCI. Bivalirudin reduced the risk of death and MI by about 30% in the few weeks after the procedure compared to heparin.

HERO-2.³² This trial compared bivalirudin to heparin in patients receiving streptokinase therapy for acute MI. The conclusion of the study was that the use of bivalirudin was associated with reduction of reinfarction rates within 96 hours, but it was not associated with reduction in mortality. It was associated with a slight increase in the risk of bleeding.

HASI.³³ This trial showed that bivalirudin is as effective as heparin in preventing ischemic complications in UA or after PCI. It was found to be superior to heparin in reducing immediate post-MI complications. In this study, bivalirudin was associated with increased incidence of bleeding. In an update of the study that was published,³⁴ bivalirudin was better than heparin in reducing death, MI, revascularization, and bleeding (as a combined endpoint) in patients with UA or post infarction angina who were undergoing PCI. The difference stemmed mainly from a reduction in the rate of revascularization.

OASIS.³⁵ This study compared lepirudin to heparin in ACS. Lepirudin reduced mortality and reinfarction at 3 days after the event compared to heparin but was associated with an increased cost and risk of major bleeding, which required transfusion.

REPLACE-II.³⁶ In this trial, bivalirudin, given during PCI as an IV bolus followed by an infusion, was compared to heparin and glycoprotein (GP) IIb/IIIa inhibitors given 12 to 18 hours after the procedure. The study was set to assess for noninferiority for primary endpoint of death, MI, urgent revascularization, or major bleeding. Bivalirudin was found to be associated with a significant reduction in major bleeding compared to heparin and GP IIb/IIIa inhibitor.

RE-LY.³⁷ This study compared warfarin to dabigatran 150 mg twice daily and dabigatran 110 mg twice daily in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was stroke or systemic embolism. Dabigatran in both doses were found to be noninferior to warfarin for primary outcome, with the 150 mg dabigatran dose superior to warfarin with similar rates of bleeding.

ACUITY.³⁸ In this trial, patients with ACS undergoing early invasive strategy were treated with one of three regimens: UFH or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Primary end-points included a composite ischemia endpoint (death, MI, and unplanned revascularization for ischemia), as well as major bleeding, and the combination of composite ischemia or major bleeding. Bivalirudin plus GP IIb/IIIa inhibitor compared to heparin plus IIb/IIIa inhibitor was found to be non-inferior for the composite ischemia endpoint as well as for major bleeding. Bivalirudin alone was found to have significantly reduced rates of major bleeding and was noninferior compared to heparin plus GP IIb/IIIa inhibitor for ischemic events.

HORIZONS-AMI.³⁹ This trial compared the use of bivalirudin to heparin plus GP IIb/IIIa inhibitor in patients with STEMI who presented within 12 hours of symptoms and were to undergo primary PCI. Major bleeding and combined adverse cardiovascular events (combination of major bleeding or major adverse cardiovascular events, including death, reinfarction, target-vessel revascularization for ischemia, and stroke) within 30 days were the two primary endpoints. The rate of net adverse clinical events with bivalirudin alone compared to heparin plus IIb/IIIa inhibitor was reduced (9.2% vs. 12.1%; RR, 0.76; 95% CI, 0.63 to 0.92; p = 0.005). Major bleeding was reduced with bivalirudin use (4.9% vs. 8.3%; RR, 0.6; 95% CI, 0.46 to 0.77; p <0.001). Rates of major adverse cardiac events were similar between the groups. The 30-day rate of death from cardiac causes was also reduced with bivalirudin (1.8% vs. 2.9%; RR, 0.66; 95% CI, 0.40 to 0.95; p = 0.03). The rate of stent thrombosis in the first 24 hours occurred more in the bivalirudin group (1.3% vs. 0.3%, p < 0.001). However, the 30-day rate of stent thrombosis was similar between the groups (2.5% vs. 1.9%, p = 0.30).

Low-Molecular-Weight Heparin: Dalteparin (Fragmin), Enoxaparin (Lovenox), Tinzaparin (Innohep)

Mechanism of Action

Each of these three drugs binds to antithrombin, increasing antithrombin’s activity.

Side Effects

Common side effects include bleeding and thrombocytopenia (type II occurs less often than with UFH but is still a concern), rash, hematoma at the injection site, and fever.

Indications and Precautions

Dalteparin is indicated for prophylaxis of DVT in high-risk patients undergoing abdominal surgery, hip replacement surgery, and patients who are immobile during acute illness. Dalteparin is also indicated in UA/non–Q-wave myocardial infarction (NQWMI) for the prevention of ischemic complications in patients on concurrent aspirin therapy. It should be avoided in patients with HIT or suspected HIT. Although there is a lower reported incidence of thrombocytopenia with LMWH than with UFH, it can still occur. Cross-reactivity of patients developing HIT type II on UFH to those receiving LMWH is >90%. Because it is cleared renally, it is contraindicated in patients with severe renal insufficiency (creatinine clearance <30 mL/min).

Enoxaparin is labeled for prevention of DVT in patients undergoing hip replacement surgery, during and following hospitalization for knee replacement surgery, or in patients undergoing abdominal surgery who are at risk for thromboembolic complications, as well as in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness. Other indications include the prevention of ischemic complications of UA and non–ST elevation and ST-elevation MIs when coadministered with aspirin. Furthermore, it is labeled for use with warfarin for inpatient treatment of acute DVT ± PE or outpatient treatment of acute DVT without PE when administered in conjunction with warfarin. Enoxaparin is renally cleared, dose reductions are required for creatinine clearance < 30 mL/min, and it has not been approved for use for patients on dialysis.

Tinzaparin is labeled for treatment of acute symptomatic DVT with or without PE when administered in conjunction with warfarin sodium. The safety and effectiveness of tinzaparin were established in hospitalized patients. The same precautions apply as for other LMWH products.

Major Clinical Trials

ESSENCE.⁴⁰ In this trial, IV UFH was compared with enoxaparin in patients with angina at rest or NQWMI. The primary end-point, the composite of risk of death, (MI, or recurrent angina at 14 days was reduced with enoxaparin by 16.2% (OR 0.8; 95% CI, 0.67 to 0.96; p = 0.02). Secondary endpoints that included the triple composite at 30 days were reduced with enoxaparin by 15% (OR 0.81; 95% CI, 0.68 to 0.96; p = 0.02). However, individual endpoints of death or MI were not significant at 14 or 30 days. Only 16.7% of patients received PCI. No difference was found in major hemorrhage or hemorrhagic stroke, although a higher risk of hemorrhage overall was found with enoxaparin versus heparin (18.4% vs. 14.2%, p = 0.001) due to the increase in minor hemorrhage at 30 days.

A to Z Trial.⁴¹ The A to Z trial compared enoxaparin to IV UFH with concomitant tirofiban and aspirin in patients with Non–ST-elevation acute coronary syndrome (NSTE-ACS). The primary endpoint composite of all-cause death, MI, or refractory ischemia for enoxaparin was 8.4% compared to UFH that was 9.4% (HR 0.88, 95% CI, 0.71 to 1.08), which met criteria for noninferiority. The rate for thrombosis in myocardial infarction (TIMI) grade bleeding was reported in 3.0% of enoxaparin patients (vs. 2.2% for UFH) p =0.13.

ASSENT-3.⁴² The safety and efficacy of tenecteplase in combination with enoxaparin, abciximab, or UFH were studied in patients with AMI. Patients received full-dose tenecteplase with enoxaparin, half-dose tenecteplase with low-dose weight-adjusted UFH and abciximab for 12 hours, or full-dose tenect-eplase with weight-adjusted UFH for 48 hours. The primary efficacy endpoint was the composite of mortality, in-hospital reinfarction, or in-hospital refractory ischemia at 30 days. The addition of in-hospital intracranial hemorrhage or in-hospital major bleeding other than intracranial bleed made up the primary plus safety endpoint. The primary endpoint for the enoxaparin, abciximab, and UFH groups were (11.4%, 11.1%, and 15.4%; p = 0.001). Enoxaparin may have performed better due to the 7-day treatment as opposed to the 48 hours of UFH. The primary efficacy and safety endpoints were enoxaparin (13.8%), abciximab (14.2%), and UFH (17.0%), p = 0.0081. There was no difference found between the groups for 30-day mortality. A significant difference was found in major bleeding other than intracranial hemorrhage with enoxaparin (3.0%), abciximab (4.3%), and UFH (2.2%), p = 0.0005. The bleeding was not found to be significantly different between the enoxaparin and UFH groups. However, the abciximab group, specifically, was found to have an increase in major bleeding compared to the UFH group, especially in patients >75 years (13.3% vs. 4.1%) and in patients with diabetes (7.0% vs. 2.2%).

EXTRACT.⁴³ Enoxaparin was compared to UFH as adjunct therapy with fibrinolytic therapy in patients with STEMI. With fibrinolytic therapy, patients received either UFH for at least 48 hours or enoxaparin. Enoxaparin was continued through the hospital stay, or a maximum of 8 days. Primary endpoint was composite of death from any cause, or nonfatal recurrent MI through 30 days that was 9.9% for enoxaparin and 12.0% for UFH (0.83 RR; 95% CI, 0.77 to 0.90, p < 0.001). There was no difference in death between enoxaparin (6.9%) and UFH (7.5%) (p = 0.11). There was a significant increase in the rate of bleeding with enoxaparin (2.1%) compared to 1.4% for UFH (1.53 RR; 95% CI, 1.23 to 1.89, p < 0.001).

SYNERGY.⁴⁴ Enoxaparin was compared to UFH for efficacy and safety in high-risk patients with non–ST-segment elevation ACS managed with an early invasive strategy. Primary endpoint of death or nonfatal MI by 30 days was 14.0% (696/4,993) in the enoxaparin group and 14.5% (722/4,985) in the UFH group (HR, 0.96; 95% CI, 0.86 to 1.06). Enoxaparin was not superior but did meet noninferiority criteria. Enoxaparin had an increase in TIMI major bleeding (9.1% vs. 7.6%, p = 0.008), but not in GUSTO (Global Utilization of Streptokinase and t-Pa for Occluded Arteries) severe bleeding (2.7% vs. 2.2%).

CALCIUM CHANNEL BLOCKERS

This class of drugs is chemically and pharmacologically diverse. Before we classify the drugs, we will review some information on the various calcium channels. The main ports of entry for calcium into the cell are via voltagegated calcium channels, which open when the membrane depolarizes. Another is a sodium–calcium channel, which moves one calcium ion out in exchange for three sodium ions entering into the cell. The electrical balance within a cell is accomplished by the sodium/potassium ATP channel. Calcium is normally stored in the sarcoplasmic reticulum, which also helps control the level of intracellular calcium. There are three types of calcium channels, L, N, and T. They differ in distribution in various tissues, duration of opening, and voltage range. Only L and T are of interest in cardiology.

L-Type Channels

L-type channels are found in heart muscle and in parts of the conducting system, smooth muscle, brain, adrenals, and kidneys. Although all calcium channel blockers bind to the calcium channel receptor, they have different binding sites. Blocking the L channels or receptors inhibits inward calcium currents into the cell, thus reducing the concentration of calcium needed for muscle contraction, which leads to smooth muscle dilation, decreasing contractility of heart muscle, slowing of the sinoatrial (SA) node firing rate, and increasing AV nodal conductance time.

T-Type Channels

T-type channels are found in blood vessels, adrenals, brain, kidneys, the heart conduction system, and in heart muscle under pathologic conditions such as cardiomyopathy. There is only one identified binding spot for medications, and blocking this receptor leads to dilation of peripheral and coronary blood vessels, thus decreasing SVR and increasing myocardial blood flow. Also, blockade of T-type channels produces a lowering of heart rate.

Mechanism of Action

The various classes of calcium channel blockers and the drugs in each class, as well as their mechanism of action, are shown in Table 61.7.

TABLE

61.7 Calcium Channel Blockers

AV, atrioventricular.

Side Effects

The side effects and contraindications for calcium channel blockers are shown in Table 61.8.

TABLE

61.8 Side Effects, Contraindications, and Major Drug Interactions of Calcium Channel Blockers

Indications and Precautions

The various preparations and respective doses along with the labeled uses are shown in Table 61.9.

TABLE

61.9 Preparations, Dosing, and Labeled Uses for Calcium Channel Blockers

^aDiltiazem and verapamil are available as IV formulations that can used in the acute management of atrial fibrillation and supraventricular tachyarrhythmias.

Mechanism of Action

Major Clinical Trials

ASCOT-BPLA.⁴⁵ The calcium channel blocker amlodipine was compared to atenolol as an antihypertensive regimen in patients with risk factors for coronary artery disease other than hypertension. The study was stopped early because the all-cause mortality rate was significantly lower with the amlodipine strategy than with the atenolol strategy. The amlodipine-based regimen was associated with reduced rates of strokes, cardiovascular death, and new-onset diabetes, and also total cardiovascular events and procedures.

DIURETICS

By definition, diuretics (except osmotic diuretics) are drugs that lead to a net loss of sodium (Na+) and water from the body. These drugs (except spironolactone) work primarily in the kidneys, acting from within the tubular lumen. Hence, for these drugs to reach their target, they are secreted into the proximal tubule. The sites of action for these drugs are shown in Figure 61.3.

FIGURE 61.3 The human nephron and the sites of action of diuretics.

Loop Diuretics

Loop diuretics are the most powerful diuretics, causing about 15% to 20% of sodium in the tubule to be excreted, hence the name “high-ceiling diuretics.”

Mechanism of Action

Loop diuretics act in the thick segment of the ascending loop of Henle and inhibit the transport of sodium out of the lumen of the nephron by blocking the chloride (Cl^-) component of the sodium/potassium/2 chloride (Na⁺/K⁺/2Cl^-) pump in the luminal membrane of the tubule. The net outcome is sodium and water loss. It is important to remember that loop diuretics gain access to the lumen of the nephron by organic acid pumping, without relying on glomerular filtration.

Side Effects

Common side effects of loop diuretics include hypokalemia, hypomagnesemia, hypochloremic metabolic alkalosis (with overdiuresis), ototoxicity (when given in high doses and in conjunction with other ototoxic drugs), hyperuricemia, allergic reaction, azotemia, hypocalcemia, and photosensitivity. They are contraindicated for use in patients with severe sulfonamide allergic reaction (except ethacrynic acid) and anuria.

Indications and Precautions

This subgroup of diuretics is labeled for use in edema to enhance diuresis. Furosemide and torsemide are also labeled for use in hypertension. Common uses are in heart failure, acute renal failure, hyperkalemia, anion overdose, and acute pulmonary edema.

Thiazide Diuretics

Mechanism of Action

Thiazide diuretics decrease active reabsorption of sodium and accompanying chloride by binding to the chloride site of the Na+/Cl^- cotransport system in the distal convoluted tubule. Furthermore, they increase calcium reabsorption in the same region of the nephron. Drugs of this class are effective at low doses, for which reason they are called “low-ceiling diuretics.”

Side Effects

Side effects of thiazide diuretics include hypokalemia, hypouricemia, glucose intolerance, hyperlipidemia, hyponatremia, allergic reaction, weakness, fatigue, and photosensitivity.

Indications and Precautions

The various drugs in this subgroup are shown in Table 61.10. Thiazides are not effective in patients with clearance <30 mL/min. Patients may be allergic to the drug if they are allergic to sulfonamide derivatives. Thiazides should be avoided in patients with elevated serum calcium levels. They have known drug interactions with lithium, NSAIDs, probenecid, digoxin, and calcium supplements.

TABLE

61.10 Preparations, Dosing,and Indications for Thiazide and Thiazide-Like Diuretics

^aAvailable as IV and oral preparation.

Major Clinical Trials

ALLHAT.^2,46 In ALLHAT, 42,419 people with stage 1 or 2 hypertension were randomized to a diuretic (chlorthalidone), an ACE-I (lisinopril), a calcium channel blocker (amlodipine), or an α-blocker (doxazosin). After 3 years, the doxazosin arm was discontinued because of an increase in heart failure. At the end of the study at 6 years, there was no difference in primary end-points (fatal coronary heart disease and nonfatal MI) or all-cause mortality among ACE-I, diuretics, and calcium channel blockers. In secondary endpoints (stroke, heart failure), however, the diuretic proved to be better than the ACE-I at preventing strokes and heart failure and was also noted to be superior to the calcium channel blocker in preventing heart failure. The diuretic was also noted to have better overall outcomes in African American patients.

INOTROPIC AGENTS AND VASOPRESSORS

The maintenance of tissue perfusion in the body depends on the availability of adequate arterial pressure, which in turn depends on adequate cardiac output and vascular tone. We will approach this group of drugs from two perspectives, that of the inotropic agents and vasopressor agents. The goal of inotropic agents is to improve contractility of the ventricle to enhance cardiac pump function. Vasopressors, as the name suggests, are aimed at supporting the failing circulation by causing vasoconstriction. Many catecholamines have both of these properties.

Inotropic Agents

Physiologically, the mechanism of inotropic response is mediated via increases in intracellular cyclic AMP (cAMP). Hence, increasing the level of cAMP directly with catecholamines, or decreasing its degradation with phosphodiesterase inhibitors, will increase the contractility of the myocardium. However, because cAMP inhibits calcium-mediated contraction of arterial smooth muscle, vasodilatation of arterial vasculature may occur.

Dopamine (Intropin)

Mechanism of Action Dopamine has mixed α-, β-, and dopaminergic (DA₁)-agonist effects. Through the α effect (α₁), it leads to vasoconstriction. Through the β effect (β₁ > β₂), it increases cAMP and cardiac contractility. Through the DA₁ and DA₂ effects, it leads to increased renal perfusion and some peripheral dilatation (at low doses).

Side Effects Common side effects of dopamine include tachycardia, arrhythmias, hypertension, headache, and nausea.

Indications and Precautions Dopamine is labeled for use in hypotension, cardiogenic shock, septic shock, and trauma. It should be given by central line because skin necrosis may occur with extravasation. It has a graded doseߝresponse curve, with lower doses causing renal vascular vasodilation, moderate doses having predominantly β₁-adrenergic effects, and higher doses causing vasoconstriction and elevations in blood pressure.

Dobutamine (Dobutrex)

Mechanism of Action Dobutamine is a relatively selective β₁ agonist, but it has much less effect on β₂ and α₁ receptors.

Side Effects Common side effects of dobutamine include tachycardia, hypo-or hypertension, ventricular arrhythmia, nausea, headache, and myocardial ischemia.

Indications and Precautions Dobutamine is labeled for use as a short-term inotropic support in patients with acute cardiac decompensation. Tachyphylaxis may occur with prolonged use. Chronic use has been associated with increased mortality.

Epinephrine (Adrenaline)

Mechanism of Action Epinephrine is a mixed α-and β-receptor agonist (β₁ = β > α). Hence it leads to increased myocardial contractility and vasoconstriction.

Side Effects Common side effects of epinephrine include tachycardia, flushing, hypertension, restlessness, exacerbation of narrow-angle glaucoma, and ventricular arrhythmia.

Indications and Precautions Epinephrine is indicated for use in ventricular standstill (cardioplegia or cardiac arrest) and shock (particularly anaphylaxis).

Isoproterenol (Isuprel)

Mechanism of Action Isoproterenol is a nonselective β-receptor agonist (β₁ > β₂). It has the most potent inotropic effect of any inotrope.

Side Effects Common side effects of isoproterenol include tachycardia and ventricular arrhythmia (the reason it is used in the electrophysiologic laboratory to stimulate tachycardia), hypotension, myocardial ischemia, mild tremor, nervousness, and flushing.

Preparation, Dosing, Indications, and Precautions Isoproterenol is labeled for use in shock, heart block, Adams–Stokes attacks, and bronchospasm. Unlabeled uses include for bradycardia and for torsades de pointes until temporary pacing can be established.

Milrinone (Primacor)

Mechanism of Action Milrinone is a phosphodiesterase inhibitor that results in increased levels of intracellular cAMP by blocking its degradation, thus increasing contractility as well as vasodilatation because of its effect on arterial smooth muscle.

Side Effects Common side effects of milrinone include hypotension, ventricular arrhythmia, supraventricular tachycardia, angina, chest pain, headache, and thrombocytopenia.

Indications and Precautions Milrinone is labeled for short-term use in the management of CHF. Similar to dobutamine, it was found to increase mortality with long-term therapy, secondary to increasing ventricular arrhythmias.

Vasopressors

Norepinephrine (Levophed)

Mechanism of Action Norepinephrine is a mixed β and α agonist (β₁ = α > β₂). Its primary effect is vasoconstriction.

Side Effects

Common side effects of norepinephrine include hypertension, headache, trembling, and ventricular arrhythmias.

Indications and Precautions

The labeled use for norepinephrine is hypotension. It should be administered via a central line because of the risk of skin necrosis with extravasation. It should also be used with caution in patients with hepatic dysfunction or ischemic bowel, because it leads to splanchnic and hepatic vasculature constriction.

Phenylephrine (Neo-Synephrine)

Mechanism of Action

Phenylephrine is a pure a-receptor agonist that has a vasoconstrictor effect.

Side Effects Common side effects include bradycardia, hypertension, and myocardial ischemia.

Indications and Precautions Phenylephrine is labeled for use in hypotension, particularly when associated with septic shock (vasodilatation), and anesthetic hypotension. Furthermore, it may be used to counter hypotension due to vasodilatation in severe obstructive hypertrophic cardiomyopathy.

NITRATES

Nitrates are a group of drugs that are a source of NO, which produces vasodilatation in the coronary circulation as well as arterioles and veins. NO mediates vasodilatation via cAMP. These effects contribute to their antianginal properties as well as their role in heart failure. Nitrates that are in use are summarized in Table 61.11.

TABLE

61.11 Nitrates: Mechanism of Action, Side Effects, Dosing, and Indications

Some of the major trials studying the role of nitrates in the treatment of heart failure are

V-HeFT I¹ The addition of hydralazine and isosorbide dinitrate (ISDN) to standard therapy (digoxin and diuretics) improved mortality and LV function compared to placebo or prazosin in patients with heart failure.

V-HeFT II.¹⁷ Hydralazine and ISDN were compared to enalapril in men with chronic CHF receiving digoxin and diuretics. In the enalapril patients, mortality at 2 years was reduced (18%) compared to H-ISDN patients (25%), p = 0.016.

A-HeFT.⁴⁷ The addition of a fixed dose of ISDN and hydralazine to standard therapy for heart failure, including neurohormonal blockers, is efficacious and increases survival among black patients with advanced heart failure.

PLATELET INHIBITORS

Thrombus formation is a complex process that involves platelets, the vasculature including collagen and tissue factors (primary hemostasis), as well as the coagulation pathways (secondary hemostasis), as shown in Figure 61.2. The initiation of thrombus formation in the arterial system mainly involves platelet aggregation with a small amount of fibrin (white clot), whereas in the venous system, it is composed mainly of fibrin and red cells (red clot). The primary functions of the platelets are to form a plug by adhesion and aggregation, as well as providing a phospholipid surface to facilitate procoagulant reaction.

For the platelets to participate in coagulation, they have to be activated. This usually happens with exposure of the platelets to collagen in the vasculature (injury). Platelets adhere to the collagen via GP Ib-IX, leading to change in shape and granular release of ADP and thromboxane. Thrombin (from the coagulation pathway), angiotensin II, norepinephrine, and contents of granules released from platelets (including ADP and serotonin) stimulate the endothelium to release calcium and hence allow platelet activation. Factors that inhibit platelet activation are prostacyclin and NO. When platelets are activated, arachidonic acid in the endothelium is transformed to thromboxane A2 (TXA2), by cyclooxygenase enzyme (COX). Thromboxane leads to more platelet activation. This step is the target for aspirin use as an antiplatelet therapy. Serotonin, thrombin, and ADP bind to receptors on the endothelium, and via secondary messengers lead to release of calcium from the endoplastic reticulm. The binding of ADP to receptors on the endothelium is the site of action for clopidogrel, prasugrel and ticlopidine as antiplatelet therapy. As mentioned earlier, when platelets are activated, TXA2 is released. TXA2 leads to the expression of GP IIb/IIIa receptors, which allows linkage of adjacent platelets (aggregation) by fibrinogen and von Willebrand factor (vWF) to the GP IIb/IIIa. The GP IIb/IIIa receptors are the site of action of IV antiplatelet therapy (abciximab, tirofiban, and eptifibatide).

Oral Antiplatelet Therapy

Cyclooxygenase Inhibitor/Aspirin

Mechanism of Action Aspirin irreversibly acetylates platelet cyclooxygenase, decreasing the formation of TXA2 from arachidonic acid.

Side Effects Side effects include bleeding, gastric ulceration, nausea/dyspepsia/heartburn, hemolytic anemia, and tinnitus (large doses or overdose).

Indications and Precautions Aspirin is labeled for analgesic, antipyretic, and anti-inflammatory use, as well as for MI, transient ischemic attacks, CVAs, and adjunct therapy for revascularization procedures (coronary artery bypass grafts, PTCA, and carotid endarterectomy) and stent implantation.

Clopidogrel (Plavix)

Mechanism of Action Clopidogrel acts by inhibiting the P2Y₁₂ component of adenosine diphosphate receptors, which decreases the expression of the GP IIb/IIIa receptors on the platelet cell surface and thereby prevents platelet aggregation.

Side Effects Common side effects of clopidogrel include bleeding, diarrhea, headache, dizziness, abdominal pain/nausea/dyspepsia, purpura, rash, and sometimes thrombocytopenia.

Indications and Precautions The drug is labeled for use in ACS and to reduce the risk of MI, stroke, and/or peripheral arterial disease in patients with a completed MI, stroke, and/or peripheral arterial disease. It reduces rates of athero-thrombotic events in patients with UA or non–ST-elevation MI who are medically managed or with PCI (with or without stent placement). Most side effects when compared to aspirin in clinical trials were less in the clopidogrel-treated group. Maximal effects are seen 3 to 7 days after initiation of therapy. Cases of thrombotic thrombocytopenic purpura (TTP) have been reported. Recent data demonstrate that clopidogrel should be continued for 12 months after coronary artery stenting with a drug-eluting stent.⁶⁴

Prasugrel (Effient)

Mechanism of Action This is a prodrug which when converted to its active metabolite, irreversibly inhibits the P2Y₁₂ portion of the ADP receptor on platelets to prevent activation of the GP IIb/IIIa receptor, reducing platelet activity.

Side Effects Common side effects include bleeding, hypertension, headache, and nausea.

Indications and Precautions Prasugrel is indicated to reduce rates of thrombotic cardiovascular events in patients with UA, NSTEMI, or STEMI managed with PCI. Due to the increased concern for bleeding, use with other anticoagulants should be cautioned. Use is contraindicated in patients with history of transient ischemic attack or stroke. Use in patients >75 years of age is not recommended due to increased risk of fatal and intracranial bleeding and uncertain benefit. For patients of low weight (<60 kg), a lower maintenance dose should be considered.

Ticagrelor (Brilinta)

Mechanism of Action This reversibly binds to the ADP P2Y₁₂ receptor to reduce platelet aggregation by inhibiting the activation of the IIb/IIIa receptor complex on platelets.

Side Effects Common side effects include major bleeding, dyspnea, and headache.

Indications and Precautions Ticagrelor is indicated for use with aspirin for secondary prevention of thrombotic events in patients with UA, NSTEMI, and STEMI who are medically managed or managed with PCI and/or coronary artery bypass graft. Use is contraindicated in patients with active pathologic bleed or presence or history of intracranial hemorrhage. Efficacy may be reduced if used with aspirin doses higher than 100 mg daily. Maintenance doses of aspirin <100 mg daily are recommended. Cardiac events may increase with premature discontinuation of therapy.

Ticlopidine (Ticlid)

Mechanism of Action See clopidogrel.

Side Effects Common side effects of ticlopidine include bleeding, diarrhea, nausea, vomiting, anorexia, rash, neutropenia, and purpura. Rare but severe life-threatening cases of neutropenia, TTP, aplastic anemia, and agranulocytosis can occur. A complete blood count with differential should be measured at baseline and every 2 weeks for the first 3 months of therapy.

Indications and Precautions The labeled use for ticlopidine is to reduce the risk of thrombotic stroke in patients with completed thrombotic stroke or stroke precursors. It is also used as adjunctive therapy for coronary artery stent placement and as an alternative to aspirin in patients who are unable to take aspirin or clopidogrel. Patients should be monitored for fevers or other signs of infection. Maximal effects are seen 3 to 7 days after initiation of therapy.

Cilostazol (Pletal)

Mechanism of Action The mechanism for intermittent claudication is not fully known. However, as an antiplatelet therapy, cilostazol acts as a phosphodiesterase III inhibitor, suppressing breakdown of cAMP and thus leading to vasodilation and platelet inhibition.

Side Effects Common side effects of cilostazol include headache, palpitations, diarrhea, peripheral edema, and dizziness.

Indications and Precautions Cilostazol is labeled for use to reduce symptoms of intermittent claudication. Unlabeled use is an adjunct to aspirin in patients receiving coronary stenting. It should be taken on an empty stomach and should not be used in patients with CHF because phosphodiesterase inhibitors have been associated with increased mortality rates in CHF patients.

Major Clinical Trials of Antiplatelet Medications

ISIS-2.⁴⁸ Aspirin and streptokinase independently reduced mortality in patients with AMI. The combination of the two drugs was better than either alone (synergistic effect) in terms of mortality, without increasing the risk of hemorrhagic stroke.

Antithrombotic Trialists’ Collaboration.⁴⁹ This was a collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high-risk patients. It found that aspirin is protective in patients who are at increased risk of AMI or ischemic stroke, or who have unstable or stable angina, previous MI, stroke or cerebral ischemia, peripheral arterial disease, or atrial fibrillation. Low-dose aspirin (75 to 150 mg daily) is an effective antiplatelet regimen for long-term use, but in acute settings, an initial loading dose of at least 150 mg aspirin may be required.

CURE.⁵⁰ The study’s goal was to assess the efficacy and safety of clopidogrel in addition to aspirin in patients with ACS without ST elevation. The study found that the long-term use of clopidogrel with aspirin reduced the risk of events in patients with ACS. The use of clopidogrel was associated with an increased risk of bleeding.

CURE-PCI.⁵¹ This trial looked at the effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing PCI. The results showed that long-term use of clopidogrel after PCI was associated with a lower rate of cardiovascular death, MI, or any revascularization.

CREDO.⁵² This trial showed that, after PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events.

CLASSICS.⁵³ This study showed that the combination of aspirin and clopidogrel was superior to the combination of aspirin and ticlopidine in terms of safety and tolerability. There was no difference in terms of impact on cardiac events.

ISAR-REACT.⁵⁴ This trial evaluated the efficacy of abciximab in 2,159 patients undergoing elective PCI. From the clopidogrel point of view, all patients were pretreated with 600 mg of clopidogrel at least 2 hours before PCI. There was no significant difference among groups that received clopidogrel at various intervals.

CLARITY-TIMI 28.⁵⁵ This trial randomized 3,491 patients (<75 years of age), presenting within 12 hours of symptoms of STEMI, to either clopidogrel (300-mg loading dose and 75 mg daily thereafter) or placebo. Clopidogrel was given after receiving aspirin and thrombolysis. The clopidogrel group had higher rates of vessel patency at angiography as well as lower rates of reinfarction at 30 days. A subgroup analysis of this study⁵⁶ looked at patients who had PCI and stenting within a few days after the clopidogrel loading and fibrinolysis. Early clopidogrel loading after fibrinolysis in patients who subsequently proceeded to PCI was associated with lower risk of cardiovascular death, MI, or stroke at 30 days.

TRITON-TIMI 38.⁵⁷ This trial compared prasugrel to clopidogrel in a randomized, double-blind fashion, in 13,608 ACS patients who were scheduled for PCI. A loading dose of prasugrel (60 mg) or clopidogrel (300 mg) was given prior to PCI followed by a maintenance dose of either prasugrel (10 mg) or clopidogrel (75 mg) daily. Aspirin use was required with recommended doses of 75 to 162 mg daily. The primary efficacy end-point was a composite (rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke). Prasugrel significantly reduced rates of the primary endpoint, as well as rates of MI, urgent target-vessel revascularization, and stent thrombosis. However, prasugrel had a significant increase in major bleeding. Patients with a history of cerebrovascular events (transient ischemic attack or stroke) had net harm with prasugrel and patients age > 75 years or weight < 60 kg did not derive a net clinical benefit with prasugrel.

PLATO.⁵⁸ In this trial, ticagrelor was compared to clopidogrel in patients with ACS, with or without ST-segment elevation for prevention of cardiovascular events. The primary endpoint was the composite of death from vascular causes, MI, or stroke, which occurred less in the ticagrelor group (9.8% of patients vs. 11.7% of patients at 12 months, HR, 0.84; 95% CI, 0.77 to 0.92; p < 0.001). All-cause mortality was also reduced with ticagrelor versus clopidogrel (4.5% vs. 5.9%, p < 0.001). For patients randomized to early invasive strategy, the primary end-point was also reduced with ticagrelor (8.9% vs. 10.6% with clopidogrel; p = 0.003). There was no significant difference in major bleeding between the groups. However, in the ticagrelor group, there was a significant increase in episodes of intracranial bleeding (26 [0.3%] vs. 14 [0.2%], p = 0.06), as well as fatal intracranial bleeding (11 [0.01%] vs. 1 [0.01%], p = 0.02). The incidence of dyspnea was greater with ticagrelor versus placebo (13.8% vs. 7.8%). In a prespecified subgroup analysis,⁵⁹ ticagrelor was found to have less of an effect in North American patients in the United States. Patients in the United States, compared to the rest of the world (ROW), were more frequently taking higher maintenance doses (>300 mg in 61% vs. 4% in ROW) of aspirin. Ticagrelor patients in the cohort on >300 mg doses of aspirin had worse primary efficacy outcomes compared to clopidogrel (HR 1.45, 95% CI, 1.01 to 2.09). Clopidogrel in combination with high- or low-dose (<100 mg daily) aspirin did not have any difference in outcomes. Ticagrelor compared to clopidogrel with low-dose aspirin had the lowest risk of cardiovascular death, MI, or stroke.

Intravenous Antiplatelet Therapy/Glycoprotein IIb/IIIa Inhibitors

Refer to Table 61.12 for details.

TABLE

61.12 Glycoprotein IIb/IIIa Inhibitors: Preparations, Mechanism of Action, and Side Effects

Major Clinical Trials

PRISM.⁶⁰ This study compared the effects of tirofiban with aspirin versus heparin with aspirin on clinical outcomes in patients with UA. There was no difference between the two groups in terms of the combined endpoints at 30 days. Mortality alone was significantly reduced in the tirofiban group.

RESTORE.⁶¹ The study focused on the effects of tirofiban on adverse cardiac events in patients with UA who were undergoing PCI. The study showed that tirofiban reduced the primary outcome, which was a composite of death, MI, PCI failure, and coronary artery bypass grafting (CABG). However, the reduction in emergency revascularization seen early in the study was no longer significant at 30 days.

TARGET.⁶² TARGET compared tirofiban and abciximab for prevention of ischemic events with PCI. Abciximab was more effective than tirofiban in preventing nonfatal MI as well as in the composite endpoint of death, MI, or urgent target vessel revascularization.

TACTICS-TIMI-18.⁶³ This trial compared early invasive to conservative therapy in patients with ACS treated with tirofiban. The study showed that the strategy of early catheterization and revascularization was associated with fewer major cardiac events than the conservative approach.

PURSUIT.⁶⁴ This study aimed to determine the effects of eptifibatide in patients with ACS between those undergoing PCI versus those being managed conservatively. The study found that eptifibatide reduced the composite endpoint of death or MI at 30 days with either strategy of management.

PURSUIT.⁶⁴ This study aimed to determine the effects of eptifibatide in patients with ACS between those undergoing PCI versus those being managed conservatively. The study found that eptifibatide reduced the composite endpoint of death or MI at 30 days with either strategy of management.

ESPIRIT.⁶⁵ This study was aimed at assessing the efficacy and safety of high-dose eptifibatide in elective coronary stent implantation. The study showed that eptifibatide reduced ischemic complications after elective stent placement, as well as the combined endpoint of death and MI.

IMPACT-II.⁶⁶ This study aimed at assessing eptifibatide impact on the prevention of ischemic complications following PCI. The study showed that the use of eptifibatide was associated with reduced early abrupt closure and reduced the rates of 30 days ischemic events without increasing the risk of bleeding. However, there was no effect on reduction of 30-day mortality or MI, or 6-month cumulative ischemic event rate.

EPIC.⁶⁷ This study showed that abciximab bolus and infusion at the time of PTCA improved outcomes for as long as 3 years. It also showed that there was reduction in NQWMI and distal embolization in patients undergoing PCI on saphenous vein grafts.

EPILOG.⁶⁸ This trial was aimed at studying whether the clinical benefit of abciximab on reducing ischemic complications in patients undergoing high-risk PCI can be extended to all patients undergoing PCI. Furthermore, the study looked at whether adjusting the heparin dose reduced the hemorrhagic complications associated with abciximab. The study showed that abciximab with low-dose heparin reduced ischemic complications in patients undergoing PCI without increasing the risk of bleeding.

EPISTENT.⁶⁹ The purpose of this trial was to compare the outcomes of stenting with or without the use of abciximab, and the outcomes of PTCA with abciximab. The study showed that abciximab significantly improved the outcome of PCI. Furthermore, PTCA with abciximab was better and safer than stenting without abciximab.

CAPTURE.⁷⁰ Abciximab infusion started 18 to 24 hours before PCI and continued for 1 hour after PCI reduced the rates of periprocedural MI and the need for revascularization in patients with UA having PTCA, without affecting the rates of MI.

RAPPORT.⁷¹ This trial showed that abciximab in the setting of primary PCI for acute STEMI did not alter the primary endpoint at 6 months—a composite endpoint of revascularization (elective or urgent), death reduction, or reinfarction. There was an increased risk of bleeding.

ADMIRAL.⁷² This trial compared the effects of early administration of abciximab before primary stenting to stenting alone without IIb/IIIa-inhibitor therapy. The results showed that early abciximab (before primary PCI for STEMI) improved vessel patency before and after stenting and at 6 months follow-up after the procedure. It was associated with improved clinical outcomes and LV function preservation compared to primary PCI alone.

THROMBOLYTICS/FIBRINOLYTICS

When the coagulation pathways are activated, there is a naturally occurring counter process of “clot dissolving” that begins spontaneously (Fig. 61.2). This process involves plasminogen activators, tissue-type plasminogen activator (t-PA), and urokinase-type plasminogen activator (u-PA). t-PA is the major player in fibrinolysis, whereas u-PA is involved in cell migration and tissue remodeling. These activators break down plasminogen to plasmin, which in turn breaks down fibrin (thrombus) to fibrin degradation products. Fibrinolytics are drugs that mimic biologic activators and hence increase the level of plasmin, which in turn enhances thrombus breakdown. The goal of this therapy is to establish reperfusion to the myocardium, brain, or lung in acute MI (STEMI), CVA, or PE, respectively.

Alteplase/t-PA (Activase)

Mechanism of Action

t-PA binds to clot-bound plasminogen to catalyze conversion to plasmin. The specificity for clot-bound plasminogen decreases systemic fibrinolysis.

Side Effects

Common side effects of t-PA include bleeding, intracranial hemorrhage (0.7%), hypotension, nausea/vomiting, and epistaxis.

Indications and Precautions

The labeled use of t-PA is for AMI, PE, and acute ischemic stroke. Acute MI patients should receive aspirin and heparin during t-PA infusion. In PE, heparin should be started at the end of the alteplase infusion. It is considered superior to streptokinase, but the risk of intracranial hemorrhage is greater than with streptokinase. Age >65 years and weight <70 kg are independent risk factors for intracranial hemorrhage.

Reteplase, r-PA (Retavase)

Mechanism of Action

r-PA is a single-stranded mutant of wild-type t-PA with action similar to that of t-PA, with less high-affinity fibrin binding but increased potency.

Side Effects

Common side effects include bleeding and intracranial hemorrhage.

Indications and Precautions

The labeled use is for AMI. Combination of half-dose reteplase and full-dose abciximab was evaluated in the GUSTO-V trial and found not to be inferior to full-dose reteplase, but there was no mortality benefit, and risk of bleeding was increased.

Streptokinase (Streptase)

Mechanism of Action\

Streptokinase binds to clots and circulating plasminogen; this complex then catalyzes the conversion of plasminogen to plasmin. It is not specific for clot-bound plasminogen and therefore produces a systemic fibrinolytic state.

Side Effects

Common side effects of streptokinase include bleeding, bronchospasm, periorbital swelling, angioedema, anaphylaxis, hypotension, rash, intracranial hemorrhage (0.2%), fever, and urticaria.

Indications and Precautions

Labeled uses of streptokinase are AMI, PE, DVT, arterial thrombosis or embolism, and occlusion of AV cannulae. Patients should not receive streptokinase if they have received anisoylated plasminogen streptokinase activator complex (APSAC) or streptokinase within the last 12 months. Heparin is not given with streptokinase; if it is needed, the heparin is initiated 4 hours after streptokinase infusion.

Tenecteplase (TNK-ase)

Mechanism of Action

Tenecteplase binds to clot-bound plasminogen to catalyze conversion to plasmin.

Side Effects

Common side effects of tenecteplase include bleeding and intracranial hemorrhage. Hypotension may occur.

Indications and Precautions

Tenecteplase is labeled for use in acute MI. It has the same rate of intracranial hemorrhage as t-PA, but it should not be used with enoxaparin in patients >75 years old. The advantage is that it can be given as a single weight-adjusted bolus injection over 5 to 10 seconds.

Major Clinic Trials

GUSTO-I.⁷³ This trial found that the mortality in patients with acute STEMI was lower in patients who received t-PA and IV heparin than in those who received streptokinase with either IV heparin or subcutaneous heparin. Furthermore, early PCI when appropriate led to improved survival of patients with MI with cardiogenic shock at 30 days.

GUSTO-III.⁷⁴ Reteplase did not show superiority over alteplase in terms of mortality benefit. The two therapies had comparable rates of hemorrhagic strokes.

GUSTO-V.⁷⁵ In this trial, half-dose reteplase was given with a 12-hour infusion of abciximab. This combination was not superior to the standard dose of reteplase in terms of mortality. The combination therapy was associated with an increased risk of bleeding complications.

VASODILATORS, MISCELLANEOUS

In this section, we discuss a more diverse group that does not fall into any specific pharmacologic class.

Hydralazine (Apresoline)

Mechanism of Action

Hydralazine works by direct relaxation of the arteriolar smooth muscle, causing a fall in blood pressure, reflex tachycardia, and an increase in cardiac output. The exact mechanism of action at a cellular level has not been determined completely.

Side Effects

Common side effects of hydralazine include palpitation, tachycardia, flushing, myocardial ischemia, nausea, vomiting, anorexia, hypotension, and drug-induced lupus-like syndrome with prolonged use.

Indications and Precautions

Hydralazine has a labeled indication for moderate to severe hypertension and unlabeled use in heart failure.

Fenoldopam (Corlopam)

Mechanism of Action

Fenoldopam is a dopamine (DA₁) receptor agonist that causes smooth muscle relaxation, leading to vasodilatation and increased renal blood flow.

Side Effects

Common side effects of fenoldopam include hypotension, headache, flushing, nausea, tachycardia, and, rarely, hypokalemia.

Indications and Precautions

Fenoldopam is labeled for use as short-term therapy for severe hypertension. It is very expensive while having similar efficacy to nitroprusside in terms of hypotensive effect.

Minoxidil (Loniten)

Mechanism of Action

Minoxidil acts as a vasodilator, primarily affecting arterial smooth muscle. It antagonizes the effect of ATP on the ATP-sensitive channel, which leads to hyperpolarization and muscle relaxation.

Side Effects

Common side effects of minoxidil include significant reflex tachycardia, sodium and water retention, weight gain, hirsutism, breast tenderness, gynecomastia, and headache.

Indications and Precautions

The labeled use for minoxidil is severe hypertension, and usually it is the last resort in treating hypertension that is not responsive to other medications. It should be used with beta-blockers to reduce the reflex tachycardia and diuretics to reduce sodium and water retention.

Nitroprusside (Nipride)

Mechanism of Action

Direct vasodilatation occurs secondary to the liberation of the nitroso group from the nitrosocyanide structure. Nitroprusside has a balanced effect on both veins and arteries.

Side Effects

Common side effects of nitroprusside include hypotension, headache, nausea, confusion, and metabolic acidosis. Less common side effects are thiocyanate and cyanide toxicity.

Preparation, Dosing, Indications, and Precautions

The labeled use for nitroprusside is hypertensive urgencies and the management of acute CHF. Patients with hepatic failure are at increased risk for developing cyanide toxicity, and this should be suspected in patients with metabolic acidosis, venous hyperoxemia, increased serum lactate levels, air hunger, confusion, seizures, and ataxia. Patients with suspected cyanide toxicity should receive inhaled amyl nitrite while being given 300 mg of sodium nitrite IV, followed by 12.5 mg of sodium thiosulfate IV. If symptoms reappear, then administer half the amounts of sodium nitrite and sodium thiosulfate again. These modalities shift cyanide conversion to thiocyanate. Cyanide levels are not helpful acutely, because it may take up to 5 days to achieve results. Thiocyanate is a neurotoxin that causes confusion, psychosis, lethargy, tinnitus, convulsions, and hyperreflexia. Hemodialysis removes thiocyanate from the blood. Levels are not typically monitored unless infusion of >3 days or when high doses are used in patients with renal failure.

Bosentan (Tracleer)

Mechanism of Action

Bosentan is an endothelin-receptor antagonist (ET-A and ET-B), which leads to vasodilatation (endothelin is a potent vasoconstrictor).

Side Effects

Common side effects of bosentan include severe hepatotoxicity (11% of patients), teratogenicity, headache, flushing, hypotension, fatigue, pruritus, edema, and anemia.

Indications and Precautions

Bosentan is labeled for management of pulmonary hypertension in patients with Class III or IV symptoms. It is necessary to monitor the liver function tests (LFTs); if there is three- to fivefold increase in these, dosage reduction or discontinuation is required. It is available only through the Tracleer Access Program (TAP), a restricted distribution program.

Ambrisentan (Letairis)

Mechanism of Action

Ambrisentan is an endothelin-receptor antagonist (ET-A and ET-B), which leads to vasodilation. Affinity for ET-A is greater than ET-B.

Side Effects

Common side effects include peripheral edema, headache, decrease in hemoglobin/hematocrit, and palpitations.

Indications and Precautions

Indicated for the treatment of pulmonary artery hypertension World Health Organization Group I for improving exercise ability and decrease rate of clinical deterioration. Ambrisentan is contraindicated in pregnancy.

Nesiritide (Natrecor)

Mechanism of Action

Nesiritide is a recombinant human b type of BNP or rhBNP. It binds to guanylate cyclase receptors in vascular smooth muscle and endothelial cells, increasing the intracellular level of cGMP and thereby causing venous and arterial vasodilatation, resulting in dose-dependent reduction in pulmonary capillary wedge pressure (PCWP) and systemic blood pressure. It also causes mild natriuresis.

Side Effects

Common side effects of nesiritide include hypotension, headache, dizziness, and renal dysfunction.

Indications and Precautions

Nesiritide is labeled for use in acutely decompensated heart failure patients who have dyspnea at rest or with minimal activity. It should be avoided in patients with cardiogenic shock, aortic stenosis, and severe hypotension (systolic blood pressure <90 mm Hg).

Major Clinic Trials

VMAC.⁷⁶ In this trial, nesiritide, intravenous nitroglycerin, or placebo was added to standard therapy for patients with dyspnea at rest due to decompensated heart failure. The primary endpoints were absolute change in PCWP (in catheterized patients) and dyspnea (all patients). Nesiritide significantly reduced PCWP at 3 hours (mean change from baseline -5.8 (6.5) mm Hg vs.placebo, p < 0.001; vs. nitroglycerin p = 0.03). At 24 hours, nesiritide reduced PCWP significantly more than nitroglycerin (-8.2 mm Hg vs. -6.3 mm Hg; p = 0.04). Dyspnea at 3 hours was improved with nesiritide over placebo (p= 0.03), but not compared to nitroglycerin (p = 0.56).

ASCEND-HF.⁷⁷ Nesiritide was compared to placebo in addition to standard care in hospitalized patients with acutely decompensated heart failure. The primary endpoints included change in dyspnea at 6 and 24 hours, and composite endpoint of rehospitalization for heart failure or death within 30 days. Nesiritide was not found to have a significant effect on dyspnea. Mortality and rehospitalization were not significantly different between the two groups. In regard to safety, hypotension occurred more frequently in the nesiritide group versus placebo (26.6% vs. 15.3%; p < 0.001) as did symptomatic hypotension (7.3% vs. 4.0%; p < 0.001).

Epoprostenol (Flolan)

Mechanism of Action

Epoprostenol is prostaglandin I₂. It is a vasodilator of the systemic as well as pulmonary arteries. It also inhibits platelet aggregation.

Side Effects

Common side effects of epoprostenol include jaw pain, hypotension, headache, rash, diarrhea, joint pain, and non-cardiogenic pulmonary edema.

Indications and Precautions

The primary use for epoprostenol is for pulmonary hypertension and pulmonary hypertension secondary to scleroderma in NYHA Class III and IV patients who have not responded to conventional therapy. The half-life of the drug is very short, 3 to 5 minutes; hence abrupt cessation is not well tolerated by patients.

Treprostinil (Remodulin)

Mechanism of Action

Treprostinil is a prostacyclin that directly vasodilates both pulmonary and systemic arterial vascular beds, as well as inhibiting platelet aggregation.

Side Effects

Common side effects include flushing, headache, rash, diarrhea, nausea, infusion site pain (subcutaneous administration), jaw pain, edema, and hypotension.

Indications and Precautions

The labeled indication is for pulmonary arterial hypertension in patients with NYHA Class II to IV symptoms to decrease exercise-associated symptoms (intravenous and subcutaneous use). Abrupt withdrawal may worsen symptoms. It may cause symptomatic hypotension. Use with caution in patients with low blood pressure.

Digoxin (Lanoxin)

Mechanism of Action

Digoxin, a digitalis glycoside, is used as adjunctive treatment for heart failure and to slow ventricular rate in patients with atrial fibrillation. Digoxin inhibits the sodium–potassium pump on the cell membrane, blocking sodium transport out of the cell, thus increasing intracellular sodium concentrations, and eventually resulting in increased intracellular levels of calcium. This results in an increase in cardiac contractility. Digoxin enhances parasympathetic tone, leading to an increase in AV nodal refractory period, as observed by increases in the P–R interval.

Side Effects

The most common side effects related to digoxin include atrial and ventricular arrhythmias, blurred vision, anorexia, nausea and vomiting, and visual color distortion.

Indications and Precautions

Digoxin is no longer first-line therapy in the treatment of heart failure unless the patient has underlying atrial fibrillation and rapid ventricular response. Patients with continued symptoms of heart failure or with frequent admissions to the hospital may be considered candidates for digoxin after they have been maximized on therapies that improve survival.

Dosing of digoxin can be challenging, as one needs to consider patient weight, renal function, and concomitant medications. The inherent half-life of digoxin is 36 hours in patients with normal creatinine clearance. In patients with impaired renal function, the half-life of digoxin increases, and it will prolong to about 5 days if the patient has end-stage renal disease (ESRD). Concomitant medications may alter digoxin levels, and therefore when initiating new medications or discontinuing medications, one needs to assess the dose. Common drug interactions include those with amiodarone, quinidine, diltiazem and verapamil, erythromycin, and clarithromycin, to name a few.

Intravenous Nitroglycerin

Mechanism of Action

Nitroglycerin liberates NO, which activates guanylyl cyclase, increasing intracellular cGMP levels. The resulting effect produces smooth muscle relaxation leading to vasodilation. Standard doses of nitroglycerin primarily produce venodilation, leading to a decrease in ventricular wall tension by lowering LV end diastolic volume.

Side Effects

The most common side effects include headache, hypotension, tachycardia or bradycardia, dizziness, and rash.

Indications and Precautions

Nitroglycerin, by decreasing myocardial oxygen demand, is typically used to treat chest pain associated with ACSs and to relieve dyspnea associated with CHF.

Nitroglycerin is rapidly metabolized in the liver to less active and inactive metabolites. Because of extensive first-pass metabolism, nitroglycerin cannot be given orally for a therapeutic effect. Sublingual, transdermal, and IV administration of nitroglycerin bypass the portal circulation, avoiding first-pass metabolism. Chronic use of nitroglycerin or isosorbide di- and mononitrates without interruptions in therapy frequently leads to tolerance. Multiple mechanisms of tolerance have been described and include cellular sulfhydryl group depletion, volume expansion, free-radical generation, and neurohormonal activation. The exact mechanism is unknown, but daily nitrate interruptions (8 to 12 hours) will restore the efficacy of nitrates.

Ranolazine (Ranexa)

Mechanism of Action

Ranolazine has antianginal and anti-ischemic effects that do not affect hemodynamics. Ranolazine causes inhibition of the late phase of the inward sodium channel (I_Na) in ischemic cardiac myocytes. This reduces intracellular sodium concentration that reduces calcium influx. Decrease in intracellular calcium causes reduction in ventricular tension and myocardial oxygen consumption.

Side Effects

Common side effects include dizziness, constipation, nausea, and headache.

Indications and Precautions

Ranolazine is indicated for the treatment of chronic stable angina. Ranolazine does not relieve acute angina. Prolongation of AT interval has been shown in a concentration-dependent manner. Patients with hepatic impairment may have more significant increases. Use is contraindicated in patients with clinically significant hepatic impairment. Use with caution in patients with renal impairment as plasma levels can increase by 50%. Ranolazine increases the levels of dabigatran, digoxin, and simvastatin. Simvastatin doses should be reduced to 20 mg daily.

Major Clinic Trials

MERLIN—TIMI 36.⁷⁸ Ranolazine was studied in NSTE-ACS patients. The primary efficacy endpoint was first occurrence of the composite of cardiovascular death, MI, or recurrent ischemia. This occurred in 696 (21.8%) ranolazine patients and 753 (23.5%) patients in the placebo group (HR, 0.92; 95% CI, 0.83 to 1.02); p = 0.11). Recurrent ischemia was significantly lower in the ranolazine group. Death from any cause was not significantly different between the groups. However, clinically significant arrhythmias during Holter monitoring in the first 7 days were lower in the ranolazine group.

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SUGGESTED READINGS

Braunwald E, et al., eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia: WB Saunders; 2012.

Fraker TD Jr, et al. 2002 Chronic Stable Angina Writing Committee. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to Develop the Focused Update of the 2002 Guidelines for the Management of Patients With Chronic Stable Angina. J Am Coll Cardiol. 2007;50:2264–2274.

Griffin BP, Topol EJ, eds. Manual of Cardiovascular Medicine. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2009.

Jessup M, et al. 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult Writing Committee. 2009 Focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;119:1977–2016.

Kloner RA, Birnabaum Y. Cardiovascular Trials Review. 8th ed. Darien: Louis F. Le Jacq; 2003.

Kloner RA, Birnabaum Y. Cardiovascular Trials Review. 9th ed. Darien: Louis F. Le Jacq; 2005.

Kushner FG, et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120:2271–2306.

Opie LH, Gersh BJ. Drugs for the Heart. Philadelphia: Elsevier; 2009.

Topol EJ, ed., Califf RM, Prystowsky RM, et al., assoc. eds. Textbook of Cardiovascular Medicine. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2006.

Wann LS, et al. 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee. 2011 A CCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57:223–242.

Wright RS, et al. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57:1920–1959.

QUESTION AND ANSWERS

Questions

1. A 52-year-old woman with a history of ischemic cardiomyopathy and congestive heart failure (CHF) is on stable doses of lisinopril, carvedilol, furosemide, and digoxin. She was admitted to the hospital with shortness of breath, orthopnea, and lower extremity edema and is bradycardic with a heart rate of 42. Her jugular venous pressure was 15 cm H₂O, with bilateral basilar crackles on lung examination. She was 5.6 L in negative fluid balance over 48 hours of hospitalization, and her symptoms were much resolved. On the third day of hospitalization, the patient described dizziness, with vitals showing bradycardia with heart rate of 45. Which of the following is the best next step?

a. Stop carvedilol.

b. Stop lisinopril.

c. Stop digoxin.

d. Reduce or decrease furosemide dose.

e. Discharge home with no change in medication.

2. A 64-year-old man presented to the emergency room with crushing chest pain that he had been experiencing for the last 20 minutes. Electrocardiogram (ECG) showed 3-mm ST elevation in leads V₁ to V₃ with reciprocal ST depression in the inferior leads. The patient received aspirin and was started on a heparin drip in the emergency room and forwarded to primary angioplasty. The patient was found to have an acute occlusion of the middle of the left anterior descending artery (LAD). The patient underwent percutaneous coronary intervention (PCI) with a Cypher stent (sirolimus-coated stent) to the middle LAD. How long should you recommend the patient take clopidogrel?

a. The patient should take 75 mg of clopidogrel for at least 6 months.

b. The patient should take 75 mg of clopidogrel for at least 3 months.

c. The patient should take 75 mg of clopidogrel for at least 12 months.

3. A 62-year-old man has a history of chronic renal insufficiency (CrCl 25 mL/min). He has had an aortic valve replacement with a St Jude mechanical prosthetic valve. In addition, he has a history of heparin-induced thrombocytopenia (HITT) complicated with pulmonary embolus. In anticipation of an elective abdominal surgery, warfarin was discontinued. The patient’s INR is now <2. Which of the following choices for anticoagulation would you recommend?

a. Argatroban, 2 mg/kg/min

b. Dabigatran 75 mg orally twice daily

c. Heparin bolus and drip per weight nomogram

d. Enoxaparin, 1 mg/kg SC every 12 hours

4. A 74-year-old male presents to your office after a recent (4 weeks ago) admission for ACS. He was discharged on medical management. He is on the following medications: aspirin 325 mg daily, atorvastatin 80 mg daily, lisinopril 40 mg daily, isosorbide mononitrate 30 mg daily, ticagrelor 90 mg twice daily, and metoprolol tartrate 50 mg twice daily. His blood pressure is 115/77 and heart rate 65 and has not experienced any additional angina and feels well. What adjustments should be made to his medications?

a. Discontinue the isosorbide mononitrate.

b. Decrease the lisinopril to 10 mg daily.

c. Decrease the aspirin to 81 mg daily.

d. Decrease the metoprolol tartrate to 25 twice daily.

5. Tolerance (tachyphylaxis) occurs with nitrates that can be avoided by:

a. Taking an aspirin 30 minutes prior to nitroglycerin dose

b. Avoiding using the transdermal patch

c. Using only low-dose nitroglycerin

d. Implementing a nitrate-free interval of 8 to 12 hours

6. A patient with normal renal function has hyperkalemia and is currently taking an angiotensin-converting enzyme inhibitor (ACE-I) for his or her hypertension. The best clinical decision would be to:

a. Discontinue the ACE-I and start a thiazide diuretic

b. Change from an ACE-I to an angiotensin receptor blocking (ARB) agent

c. Add a thiazide diuretic to the ACE-I

d. Add a renin inhibitor

7. An 80-year-old female presents to the emergency department with non–ST-elevation myocardial infarction (NSTEMI) and is being transported for PCI. Her past medical history includes hypertension, atrial fibrillation, stroke, and diabetes. Which antiplatelet option would you choose to initiate?

a. Prasugrel 60-mg loading dose and 5-mg daily dose

b. Clopidogrel 600-mg loading dose and 75 mg daily

c. Prasugrel 60-mg loading dose and 10 mg daily

8. A 56-year-old female with end-stage renal disease (ESRD) on hemodialysis (HD) presents with atrial fibrillation with a rapid ventricular response and is undergoing a transesophageal echo and cardioversion. Your choice of anticoagulation prior to cardioversion is:

a. Enoxaparin 1 mg/kg twice daily

b. Dabigatran 75 mg twice daily

c. Enoxaparin 1 mg/kg once daily

d. Unfractionated heparin (UFH) infusion

9. A 61-year-old female with a previous history of coronary artery disease, myocardial infarction (MI), CHF (ejection fraction 25%), and chronic renal insufficiency (CrCl 35 mL/min) presents to your office as recommended by her primary care physician. Her current medications include aspirin 81 mg daily, atorvastatin 40 mg daily, lisinopril 40 mg daily, and atenolol 50 mg daily. She states that she has been feeling more tired recently. Her renal function is stable and her potassium is within normal limits. Her vitals show blood pressure of 110/78 and heart rate of 46. What adjustments should be made to her medications?

a. Decrease lisinopril dose.

b. Discontinue lisinopril and initiate ISDN and hydralazine combination.

c. Decrease atenolol dose.

d. Change atenolol to metoprolol succinate XL 50 mg daily.

10. A 68-year-old male with coronary artery disease, hypertension, and hyperlipidemia presents to your office for follow-up. He is currently taking metoprolol tartrate 100 mg twice daily, lisinopril 20 mg daily, simvastatin 40 mg daily, aspirin 81 mg daily, amlodipine 10 mg daily, and ranolazine 1,000 mg twice daily. His lipid panel shows low-density lipoprotein (LDL) of 85 mg/dL with a goal LDL of <70 mg/dL. How should his lipid-lowering therapy be modified?

a. Change to atorvastatin 40 mg.

b. Increase simvastatin to 80 mg.

c. Add ezetimibe.

d. Add fenofibrate.

Answers

1. Answer C: Digoxin has not shown survival benefit in heart failure, can cause bradycardia, and should be discontinued. The patient has been on stable doses of standard heart failure medications shown to reduce mortality (ACE-I, beta-blocker). Although carvedilol can reduce heart rate, without the interaction with the digoxin, the heart rate should improve. Furosemide does not cause bradycardia.

2. Answer C: Though previous guidelines recommended taking 75 mg of clopidogrel for 3 months after stenting with a sirolimus-eluting stent and for 6 months after a paclitaxel-eluting stent, the current guidelines recommend at least 12 months.

3. Answer A: Argatroban is recommended because the patient has chronic renal insufficiency and argatroban is cleared hepatically. Choice b, dabigatran, is cleared renally, and the patient has a mechanical aortic valve as well as HITT, which dabigatran has not been evaluated or approved for. Heparin is contraindicated because the patient has a history of HITT and is at increased risk for thrombotic complications, particularly with prosthetic valve. Enoxaparin is not advised because there is a significant degree of cross-reactivity with UFH with regard to HITT and concern with the dose not being renally adjusted.

4. Answer C: It is recommended to use doses of aspirin <100 mg daily for maintenance therapy when in combination with ticagrelor. In the prespecified subgroup analysis of the PLATO trial,⁵⁹ ticagrelor was found to have less of an effect in North American patients in the United States. Ticagrelor patients for the cohort on >300 mg doses of aspirin had worse primary efficacy outcomes compared to clopidogrel. Ticagrelor compared to clopidogrel with low-dose aspirin had the lowest risk of cardiovascular death, MI, or stroke. The patient’s vitals are stable and he has no side effects from his other medications, so there is no need to discontinue or decrease doses of his other medications.

5. Answer D: Tachyphylaxis can be avoided by including a nitrate-free interval.

6. Answer A: Thiazide diuretics are considered first-line therapy for hypertension for patients without compelling indications such as heart failure, diabetes, and ischemic heart disease. Adding the thiazide to the ACE may cause hypotension but may not correct the hyperkalemia. Changing to an ARB or adding a renin inhibitor would also potentiate hyperkalemia.

7. Answer B: Clopidogrel is the optimal choice because in the TRITON-TIMI 38⁵⁷ trial, patients with a history of cerebrovascular events (transient ischemic attack or stroke) had net harm with prasugrel with an increased risk of bleeding compared to clopidogrel. Patients age > 75 years or weight < 60 kg did not derive a net clinical benefit with prasugrel compared to clopidogrel. Therefore, prasugrel is not recommended for use in patients >75 years old and is contraindicated in patients with a history of stroke. It is recommended by the manufacturer to lower prasugrel maintenance dose to 5 mg daily for patients who weigh <60 kg, although this is not supported by existing clinical trial data.

8. Answer D: UFH infusion should be used because it is not renally cleared and can be utilized for ESRD patients on HD. Enoxaparin is not approved for use in dialysis patients. If the patient was not on dialysis and CrCl was < 30 mL/min, enoxaparin 1 mg/kg once daily would be appropriate. Dabigatran is not recommended in patients with CrCl <15 mL/min or on HD. For patients not on dialysis with CrCl 15 to 30 mL/min, dabigatran 75 mg twice daily would be appropriate.

9. Answer D: Metoprolol succinate is approved for and has shown mortality benefit in patients with heart failure, whereas atenolol is not approved for treatment of heart failure. Atenolol is renally cleared and may be causing her bradycardia and fatigue symptoms due to accumulation of drug with her renal insufficiency. Decreasing the lisinopril dose or changing to the combination of ISDN and hydralazine is not necessary with a stable blood pressure and no signs of hyperkalemia or worsening renal failure.

10. Answer A: Changing to atorvastatin 40 mg will intensify the LDL lowering by adding the more potent agent at a higher dose without the potential risk of increased side effects or drug interactions. Amlodipine and ranolazine both have drug interactions with simvastatin in the face of new contraindications for increasing simvastatin dose above 10 mg daily in combination with amlodipine or 20 mg daily in combination with ranolazine. The current simvastatin dose (40 mg) is still too high with both drug interactions. Adding fenofibrate would potentially increase risk for myopathies, myalgias, and rhabdomyolysis. If adding ezetimibe, the dose of simvastatin would still be above the recommended maximum.