1.1 Diuretics
❑ INTRODUCTION
The era of modern diuretic therapy in cardiovascular disease emerged in the late 1950s with the development of effective oral agents with improved tolerability. Until then, the only diuretics available had been intravenous or intramuscular mercurial derivatives, limited by difficulty in use and an unfavorable toxicity profile. Today, the diuretic compounds are recognized as powerful tools that impair sodium reabsorption in the renal tubules. In doing so, they increase the fractional excretion of sodium, affect the rate of urine formation and alter long-term sodium balance. After more than 50 years in clinical use, diuretics remain of considerable importance in the management of cardiovascular diseases. Diuretics have uses other than in hypertension and edematous disorders, such as in the treatment of hypercalcemia, diabetes insipidus, glaucoma, and cerebral edema.
❑ CLASSIFICATION OF THE DIURETIC COMPOUNDS
Modern diuretic compounds are now viewed as a heterogeneous class of drugs that differ remarkably in several aspects, including their chemical derivation, mechanism, and therapeutic efficacy. The most common and clinically useful classification of diuretics is to group them into one of several categories on the basis of the primary site of their interference with sodium reabsorption (Fig. 1):
- Carbonic anhydrase inhibitors (e.g. acetazolamide), acting in the proximal tubule
- High-ceiling or “loop” diuretics (e.g. furosemide, bumetanide, torsemide), acting in thick ascending limb of the loop of Henle
- Thiazide and thiazide-like diuretics (e.g. hydrochlorothiazide, chlorthalidone, metolazone, indapamide) acting in the early portion of the distal convoluted tubule
- A fourth category, which are primarily utilized for their potassium-sparing capabilities, can further be subclassified into the sodium channel blockers (e.g. amiloride, triamterene) and the mineralocorticoid antagonists (e.g. spironolactone, eplerenone). These agents act in the late distal tubule and collecting duct
- A final category of diuretics, the osmotic agents (e.g. mannitol), interfere with sodium reabsorption throughout all segments of the nephron by creating an osmotic force throughout the length of the renal tubule. Distinguishing the diuretic compounds according to their primary site of action is important, as their therapeutic efficacy and primary clinical indications are not completely interchangeable (Table 1).
FIGURE 1: Diuretic sites of action in the nephron (Na+: Sodium; Cl−: Chloride; K: Potassium; NaHCO3: Sodium bicarbonate; numbers in parentheses reflect the relative percentage of the sodium load reabsorbed in that segment)
Recognizing their sites of action also provides an avenue for additive effects that can be obtained when the different classes of diuretics are used in combination (i.e. “sequential nephron blockade”) in certain types of patients.
❑ CLINICAL PHARMACOLOGY OF THE DIURETIC COMPOUNDS
General Pharmacokinetic and Pharmacodynamic Principles
Some generalizations can be made about the pharmacology of the diuretics, despite heterogeneity by class and agent.
- At physiologic pH, diuretics are either organic anions (loops and thiazides) or cations (amiloride and triamterene)
- All diuretics, except mannitol, are highly protein bound, which limits filtration at the glomerulus and traps the diuretic in the vascular space; therefore, they must be actively secreted into the proximal tubule lumen to exert their effect.
- Active transport into the lumen occurs via an organic acid secretory pathway for the carbonic anhydrase inhibitors, loops and thiazides, and a parallel pathway for organic bases
- Mannitol and spironolactone are exceptions; mannitol is freely filtered at the glomerulus and passes through the nephron, acting as a nonreabsorbable solute drawing water along with it, while spironolactone (although protein-bound) enters the renal tubules from plasma by competitively inhibiting the binding of aldosterone to the mineralocorticoid receptor at the basolateral surface3
- For the most part, diuretics have direct actions that are site-specific, acting on one or another of the tubular segments but not all of them
- A few agents maintain a degree of secondary activity at another segment (e.g. some thiazides also inhibit carbonic anhydrase), but it is generally considered an irrelevant contribution to their overall therapeutic effect. This is because diuretic action at one site induces important adaptive changes in other segments of the kidney that attempt to preserve sodium, thereby, minimizing the contribution of any secondary site of action to the overall natriuretic effect.
FIGURE 2: Pharmacodynamic illustration of the relationship between diuretic dose and response
* Nephrotic syndrome, congestive heart failure, cirrhosis
** Determinants of diuretic threshold and efficacy include: dose, bioavailability; tubular secretory capacity rate of absorption and time course of delivery. After identifying the threshold dose to achieve effect, a higher diuretic concentration [A] leads to significant natriuresis. When severe sodium retention occurs or sodium intake is reduced, the curve shifts to the right and the previous diuretic serum concentration achieved by the dose in [A] is no longer effective [B]. The dose of the diuretic must be increased to achieve clinically effective natriuresis [C]. Increasing the frequency of doses has no effect on sodium excretion as long as each dose is below the threshold
In general, the desired response is to obtain some meaningful level of natriuresis, which can either correspond to a significant diuresis and reduction in extracellular volume as in the case of loop diuretics to relieve edematous states or a more prolonged low-level diuresis, which reduces systemic vascular resistance and lowers blood pressure, as in the use of thiazides for hypertension. When administered intravenously, bioavailability issues are not present; however, when given orally, diuretic response will be influenced by the rate and extent of absorption, which can be highly variable among diuretic compounds and individual patients. The best index approximating diuretic drug delivery to the intraluminal site of action is its urinary excretion rate, as this corresponds to the observed natriuretic response. This relationship exists for both loops and thiazides (although shallower for thiazides) and can be illustrated using a typical sigmoidal curve (Fig. 2) where the critical determinants are basal response, dose causing 50% response, upper asymptote (maximal response) and slope.
The plasma half-life of a diuretic governs both its expected duration of action and dosing frequency. Loop diuretics have very short half-lives and must be dosed multiple times per day, while thiazides and other distally acting diuretics have half-lives that are sufficient for them to be dosed once or twice daily.
❑ ADAPTIVE RESPONSES TO DIURETIC ADMINISTRATION
The “braking” phenomenon is a term, commonly used to refer to the short-term and long-term adaptive changes observed in the nephron as a result of diuretic administration. These changes are natural compensations intended to protect intravascular volume. Their net result is to stabilize volume losses that lead to the tolerance of the diuretic effect. Diuretic tolerance should be distinguished 5clinically from diuretic resistance states, the latter describing a phenomenon occurring in conjunction with pathophysiologic conditions, such as renal failure, nephrotic syndrome, congestive heart failure, and cirrhosis. The mechanism of resistance in the setting of these comorbidities is more aptly explained by altered pharmacokinetics and pharmacodynamics rather than physiologic adaptations.
❑ INDIVIDUAL DIURETIC CLASSES
Carbonic Anhydrase Inhibitors
Carbonic anhydrase catalyzes the hydration of bicarbonate in the proximal tubule, thereby, facilitating its reabsorption. Normally, sodium reabsorption accompanies bicarbonate in this process. Inhibitors of carbonic anhydrase (Table 1) interfere with this enzyme activity in the brush border and inside the epithelial cells of the proximal tubule, resulting in impaired sodium, bicarbonate and water reabsorption, as well as a brisk alkaline diuresis. As the majority of the filtered sodium load is reabsorbed in the proximal tubule, one would ordinarily expect a proximally acting agent to produce a substantial diuretic response. However, the net diuretic effect of carbonic anhydrase inhibitors is limited because sodium that is reabsorbed distal to the proximal tubule (mainly in the thick ascending limb of the loop of Henle) offsets these losses. Additionally, the kidney compensates in several ways, which serve to diminish the overall carbonic anhydrase-dependent component of sodium reabsorption. Sodium rejected proximally increases its delivery to the macula densa, which activates the tubuloglomerular feedback mechanism, suppressing the glomerular filtration rate and amount of solutes filtered. Furthermore, the alkaline diuresis caused by the carbonic anhydrase inhibitor reduces bicarbonate levels in the serum, which results in overall less bicarbonate filtration. Acetazolamide (Table 2) demonstrates the most favorable diuretic features among several chemical derivatives of sulfanilamide that were synthesized while searching for more potent carbonic anhydrase inhibitors.
The primary uses of acetazolamide are not directly related to its diuretic action, but rather in the systemic metabolic acidosis induced as a byproduct. This can be helpful in remedying iatrogenic metabolic alkalosis occasionally caused by high doses of loop diuretics (typically in patients with cardiogenic pulmonary edema). Correcting alkalosis in these situations may improve oxygenation.
Additionally, other clinical applications of acetazolamide involve carbonic anhydrase-dependent bicarbonate transport occurring outside the kidney. As carbonic anhydrase is involved in intraocular fluid formation, acetazolamide and its derivatives can be used to decrease intraocular pressure in patients with glaucoma. Acetazolamide has also proven effective in treatment and prophylaxis of acute mountain sickness.
Loop or High-ceiling Diuretics
Loop diuretics (Table 1), so named for their site of action in the thick ascending limb of the loop of Henle. Two agents, furosemide and ethacrynic acid, were developed independently around the same time. Among this group, furosemide was introduced first, followed later by bumetanide and torsemide. The identification and development of these compounds were heralded as major advances in diuretic therapy, as their sizeable effect proved useful in renal insufficiency and heart failure patients unresponsive to other agents. Loop diuretics are often referred to as “high-ceiling” agents due to the substantial diuresis they can cause; maximally effective doses can lead to excretion of 20–25% of filtered sodium, blocking nearly all of the reabsorption occurring in this segment.6
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Located within the apical membrane of epithelial cells of the thick ascending limb is the electroneutral Na+ /K+ /2Cl− cotransporter, which passively carries sodium, potassium, and chloride ions into the cell based on the electrochemical Na+ gradient generated by the Na+ /K+- ATPase pump of the basolateral membrane. Some potassium is returned to the lumen via K+ channels of the luminal membrane, such that the net effect of this pathway is Na+Cl− reabsorption and a voltage across the tubular wall oriented with the lumen positive in relation to the interstitium. Mechanistically, loop diuretics bind to Na+ /K+ /2Cl− cotransporter at the chloride site, causing a diuresis of Na+ Cl− and K+ Cl−. In addition to prevent its reabsorption, potassium secretion from distal tubular sites is also promoted by loop diuretics by virtue of the increased delivery of sodium to these sites.
All are extensively bound to serum albumin (>95%) and must gain access to the tubular lumen by active secretion through probenecid-sensitive organic anion transporters located in the proximal tubule. This process may be slowed by elevated levels of endogenous organic acids, such as in chronic kidney disease as well as drugs that share the same transporter, including salicylates and nonsteroidal anti-inflammatory drugs.
Thiazide and the Thiazide-like Diuretics
Thiazide diuretics (Table 1) were serendipitously discovered while chemically modifying the sulfa nucleus of acetazolamide in an attempt to develop more potent inhibitors of carbonic anhydrase. The finding that it produced increased chloride rather than bicarbonate accompanying sodium in the urine was an unanticipated consequence, but a major advancement that paved the way for further advances in diuretic therapy. Chlorothiazide, the prototype of the class, became available in 1957, effectively beginning the modern era of diuretic therapy and rendering obsolete the organometallic compounds previously available. Thiazide diuretics inhibit sodium reabsorption from the luminal side in the early segments of the distal tubule, by interfering with the electroneutral Na+ Cl− symporter located in the apical membrane. The increased delivery of sodium to the collecting duct also increases the exchange with potassium, leading to potassium depletion. Magnesium excretion is also increased with thiazide administration. With few exceptions, the pharmacokinetic parameters of thiazides are not uniformly characterized (Table 2). Generally, all are orally absorbed, have volumes of distribution equal to or greater than equivalent body weight and are extensively bound to plasma proteins. 1 Thiazides must actively be secreted into the proximal tubule, as they are highly protein bound and subject to limited glomerular filtration. Thiazides compete with uric acid for secretion into the proximal tubule by the organic acid secretory system; this leads to reduced uric acid excretion and can precipitate gout in predisposed individuals. Despite heterogeneity in their structure–activity relationships, which has given rise to designations of the analogues as either being thiazide-type or thiazide-like, the general designation of thiazide diuretic is inclusive of all diuretics sharing primary action in the distal tubule. An exception is indapamide, which has less direct evidence for activity at the Na+ Cl− symporter and has been suggested to possess vasodilatory effects. All thiazides have demonstrated parallel dose-response curves and comparable maximal chloruretic effects. In general, their dose-response curve is much shallower than that of loops (Fig. 2), such that there is a little difference in efficacy between the lowest and maximally effective doses.9
There is a significant variation in the metabolism, bioavailability and plasma half-lives of the thiazides (Table 2). The latter two pharmacokinetic features are the most clinically relevant parameters, as they influence the dose and frequency of administration. Chlorothiazide is relatively lipid insoluble and requires large doses to achieve concentrations, which are high enough for the drug to arrive at its site of action. Hydrochlorothiazide, the most widely used thiazide in the United States, has improved bioavailability with approximately 60–70% absorbed orally. Chlorthalidone and metolazone are subjected to a mixed pathway of primarily renal (50–80%) with minor biliary excretion (10%). Other than the 50% reduction in hydrochlorothiazide absorption, noted in patients with heart failure, almost no information exists regarding the influence of disease on the pharmacokinetics of thiazides. As the distal tubule only reabsorbs about 5% of the filtered sodium load, the overt diuretic efficacy of thiazides for volume removal in edematous disorders is limited. However, relative to the loop and other diuretics, an advantage of the thiazides is their long duration of action. This property is a major determinant allowing them to distinguish themselves primarily for their use as antihypertensive agents.
The duration of antihypertensive effect for thiazides exceeds that of their diuretic effect, mainly due to the important hemodynamic changes induced by the prolonged low-level diuresis. These hemodynamic effects can be separated into acute (1–2 weeks) and chronic (several months) periods (Fig. 3).
After commencing regular dosing of a thiazide, blood pressure-lowering is initially attributed to extracellular fluid contraction and reduction in plasma volume. The accompanying decrease in venous return depresses cardiac preload and output, thereby, reducing blood pressure. However, there is a clear dissociation between the degree of initial diuresis and antihypertensive effect, as the eventual chronic response to thiazides cannot be reliably predicted by the degree of initial fall in plasma volume. Other significant changes occurring acutely include a transient rise in peripheral vascular resistance, likely the result of counterregulatory activation of sympathetic nervous and RAAS systems.10
Potassium-sparing Diuretics
In the distal tubule and collecting ducts, sodium is reabsorbed through an aldosterone-sensitive sodium channel and by activation of an ATP-dependent sodium–potassium pump. With the help of both mechanisms, potassium and hydrogen are secreted into the lumen to preserve electroneutrality.1 Potassium-sparing diuretics are divided into two distinct classes:
- Those acting as direct antagonists of cytoplasmic mineralocorticoid receptors and
- Those acting independent of mineralocorticoids.
All potassium-sparing diuretics act primarily at the cortical part of the collecting duct and to a lesser extent in the final segment of the distal convoluted tubule and connecting tubule. As only a small amount of sodium is reabsorbed here, these agents are capable of limited natriuresis (excluding states of mineralocorticoid excess) in most patients. Their primary clinical utility resides in their potassium-sparing capabilities and to a lesser extent, their ability to correct magnesium deficiencies. Spironolactone and eplerenone (Table 2) are competitive antagonists of aldosterone, the most potent of the naturally occurring mineralocorticoids and thereby interfere with the aldosterone mediated exchange of sodium for potassium and hydrogen. Both drugs are rarely used alone, but rather in combination with other diuretics to avoid potassium deficiency. Their aldosterone-blocking capabilities also make them a primary therapy in patients with essential hypertension due to mineralocorticoid excess, such as in primary aldosteronism due to bilateral adrenal hyperplasia or in patients with aldosterone producing adrenal adenomas awaiting surgical resection, or those who are nonsurgical candidates.
The major adverse effects of spironolactone are antiandrogenic and stem from the fact that it is a steroid that competitively inhibits testosterone and progesterone at the cellular level. In particular, gynecomastia can become a concern, especially with high doses. In the dose range of 12.5–50 mg/day, it is rarely a problem. Eplerenone appears to have more selectivity for aldosterone receptors and less affinity for androgen and progestin receptors than spironolactone. Cost differences have traditionally favored spironolactone and it remains to be determined whether eplerenone's safety and efficacy constitute significant advancements over spironolactone. The actions of amiloride and triamterene (Table 2) are quite different than spironolactone and eplerenone. Triamterene has a short half-life (3–6 hours) and duration of effect. Ideally, it should be dosed multiple times per day; however, because it is most commonly used in a fixed-dose combination with hydrochlorothiazide, it is rarely dosed more frequently than once daily. Triamterene is a potential nephrotoxin associated with formation of crystals, nephrolithiasis, interstitial nephritis and acute renal failure. It must be used carefully when other potentially nephrotoxic drugs are coadministered. Amiloride has a much longer half-life (17–26 hours) and can be dosed once or twice daily, achieving steady state in approximately two days. It is preferred in patients with liver disease, as there is no required metabolic activation. However, it is extensively renally cleared and accumulates rapidly when administered in patients with chronic kidney disease.
Osmotic Diuretics
The osmotic diuretic, mannitol (Table 2), is freely filtered through the glomerulus and poorly absorbed. As it is not reabsorbed in the nephron, mannitol does not interfere with specific tubular electrolyte transport systems. Rather, it increases osmolality, as it remains in the tubule lumen and thus impairs the tubular water reabsorption normally driven by the osmotic gradient. As the medullary solute 11gradient is lost, the urinary concentrating ability of the kidney is greatly reduced and tubular fluid is diluted. The osmotic diuresis that prevails is similar to the glucose-mediated osmotic polyuria and diuresis observed in patients with uncontrolled diabetes. Although some excretion of bicarbonate occurs in the proximal tubule, mannitol's effect is largely in promoting sodium and chloride wasting in the loop of Henle.
Mannitol has been used as a preventive measure against acute renal failure in patients receiving cisplatin, radiocontrast exposure or other high-risk situations; however, there is no evidence that it is any more effective than insuring adequate volume status with parenteral fluids, a more appropriate strategy. In the same manner, mannitol has been investigated for use in oliguric acute renal failure to promote diuresis; again, limited data support this strategy and insuring adequate volume status is a more appropriate approach. Given its significant limitations, mannitol should be only rarely used as a diuretic.
❑ CLINICAL USE OF DIURETICS IN CARDIOVASCULAR DISEASES
Aside from their chemical and mechanistic classifications, diuretics can be categorized functionally into one of three primary uses:
- Treatment of essential hypertension
- Volume removal in edematous disorders
- Correction of potassium and magnesium deficiencies.
Different classes of diuretics are used for a variety of indications, and certain diuretics are more effective on managing a particular condition:
- Thiazide diuretics appear to be the most effective diuretics over the long-term in lowering blood pressure in patients with hypertension
- Loop diuretics are the most powerful diuretics to evoke a substantial diuresis; therefore, they are agents of choice for symptomatic relief in patients with edematous disorders such as congestive heart failure, cirrhosis, and nephrotic syndrome
- Potassium-sparing agents are largely reserved for correcting potassium and magnesium deficiencies associated with thiazide diuretic administration.
While only one type of diuretic is generally used at a time, there are several conditions where diuretic tolerance is encountered. In these situations, combinations of two different types of diuretics are often employed to improve response.
Diuretic Use in Hypertension
General Considerations
Thiazides have been a mainstay in the treatment of hypertension for many years and are preferred agents for chronic therapy in most hypertensive patients where a diuretic is indicated. Thiazide administration typically results in a 10–15/5–10 mm Hg reduction in blood pressure compared to placebo. Thiazide responders are often referred to as having low-renin or salt-sensitive hypertension, in deference to the large contribution volume and sodium play in the maintenance of their blood pressure. These patients typically include the elderly, blacks and high cardiac output states, such as obesity. Although the aforementioned groups are often considered more likely to respond to thiazides, an advantage of thiazides is that they can be effectively combined with nearly any antihypertensive, producing a blood pressure-lowering effect that is additive of the two individual components in almost all cases.12
Given their ability to augment efficacy of nearly all other types of antihypertensives, thiazides are powerful tools, which improve the capability of achieving blood pressure goals. In patients considered to have resistant hypertension, lack of appropriate diuretic use has been identified as the primary drug-related cause. Thiazide dosing has evolved in parallel to our progressive understanding of their mechanism of action and dose-response relationships. The dose-response curve for thiazides is much shallower than originally believed. Thiazides are now utilized in significantly lower doses and the term low-dose thiazide has become synonymous with 12.5–25 mg/day of hydrochlorothiazide or its equivalent.
Comparative Efficacy
The ability of thiazides to effectively lower blood pressure translates into reductions in cardiovascular events. Beginning with the completion of the landmark Veteran's Affairs Cooperative Group study in 1967 and continuing through the early 1990s, a series of randomized placebo-controlled trials involving more than 47,000 hypertensive patients convincingly demonstrated these effects. Combined meta-analyses and systematic review show that thiazide-based regimens reduce relative rates of heart failure by 41–49%, stroke by approximately 29–38%, coronary heart disease by 14–21% and overall mortality by 10–11% compared to placebo. Effect sizes are homogeneous throughout major subgroups of patients, including by gender, age and presence of diabetes. The results of these studies have collectively formed the basis for the recommendations contained in the first seven guideline reports of the Joint National Committee, all advocating thiazides as initial therapy for most patients.
Special Considerations
An important clinical issue with thiazides is that they are generally considered less effective in renal insufficiency, particularly when GFR falls below 40 mL/min/1.73 m2. Larger doses of thiazides have been shown to induce diuresis in patients with chronic kidney disease, but the efficacy of thiazides in this setting has a specific ceiling, which is controlled by several factors, including the reduced delivery of filtered solute and drug to the distal tubule site of action and the fact that the distal tubule is responsible for only a small amount of sodium reabsorption even under normal circumstances. Additionally, increasing the doses of thiazides is impractical given the risk of metabolic and electrolyte side effects.
In the absence of states of mineralocorticoid excess or certain rare genetic conditions, the primary role of potassium-sparing diuretics in the treatment of hypertension is that of an ancillary to help offset the potassium and magnesium wasting induced by thiazides. Spironolactone is advantageous not only in that it can correct thiazide-induced potassium and magnesium wasting, but low doses of 12.5–50 mg daily show significant additive hypotensive effects in patients resistant to treatment regardless of ethnicity or baseline aldosterone level.
Diuretic Use in Edematous Disorders
General Considerations
Loop diuretics are the most potent diuretics available, making them agents of choice in patients with edematous disorders, such as renal insufficiency, hepatic cirrhosis, congestive heart failure and nephrotic syndrome. Loop diuretics are preferred for hypertension or volume control in patients with chronic kidney disease.13
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As previously discussed, the pharmacodynamics of diuretics is altered in most edematous conditions; namely, such that maximal response is lower (Fig. 2). The mechanisms underlying this decreased responsiveness are uncertain, but may relate to increased proximal or distal reabsorption of sodium or an upregulation of the Na+ /K+ /2Cl− transporter. From a clinical perspective, this means that administering larger single doses will not improve the diuretic response. As in normal patients, it is best to first start with small doses and then titrates upward according to response. This can be achieved practically by sequentially doubling the dose until response is observed or a ceiling dose is reached (Table 3). Escalating doses above these ceiling doses will result in no additional benefit but an increase in side effects. If response is suboptimal, other strategies, such as continuous infusion or using combinations of diuretics as outlined below, may be tried.
Renal Insufficiency
In the absence of heart failure, cirrhosis or nephrotic syndrome, dysregulation of volume homeostasis is usually a late manifestation of renal insufficiency, often not developing until GFR falls to less than 10 mL/min. As renal function declines, the ability to maintain sodium balance diminishes and the fraction of filtered sodium that must be excreted to maintain sodium balance rises progressively. In the setting of constant sodium intake, fractional excretion of sodium must increase fivefold when GFR falls to 20% of normal and tenfold when GFR is 10% of normal. 14Normal kidneys are able to accommodate this over a wide range of sodium intake, but patients with renal insufficiency have limited ability to raise the fractional excretion of sodium above 50%. Assuming sodium intake exceeds this reduced maximal excretion, extracellular fluid volume expands, and edema develops. Large doses of thiazides can induce a modest diuresis in patients with renal disease, but loop diuretics are preferred, because they produce a more vigorous and reliable response. Renal clearance of loops falls in parallel with GFR because of decreased renal mass and accumulation of organic acids that compete for proximal secretion. Only 10–20% as much drug may be secreted into the tubular lumen in a patient with a creatinine clearance of 15 mL/min, compared to one with normal renal function. That said, response to the diuretic expressed as fractional excretion of sodium is similar for patients with renal insufficiency to that of healthy patients; thus, residual nephrons seem to respond normally, but the problem is in getting enough drug to the site of action to achieve the diuretic threshold.
Of the thiazides, metolazone is frequently selected for use in combination with a loop because of its long half-life and preserved activity in renal insufficiency. Rarely acetazolamide and collecting duct agents, such as spironolactone and amiloride, are used, but their response is less dramatic than that of a thiazide.
Cirrhosis
Secondary hyperaldosteronism plays an important role in the pathogenesis of sodium retention in patients with cirrhotic edema. Spironolactone is the mainstay of therapy in such patients. Not only it increases patient comfort, but it can also eliminate the need or reduce the interval between paracenteses, an advantage is that protein normally removed during paracenteses can also be spared. The usual dosing range of spironolactone is 50–400 mg/day, but doses above 200 mg/day are often not well tolerated due to painful gynecomastia. An advantage of spironolactone is the once-daily dosing made possible by the sufficiently long half-lives of its active metabolites.
Cirrhotic patients with edema receiving diuretics are prone to complications such as intravascular volume depletion and prerenal azotemia, in up to 20% of patients. Once euvolemia is achieved, maximal diuresis should be limited to 500 mL/day. As in other conditions in which combinations of diuretics are used, close monitoring of electrolytes is necessary. Diuretic therapy should be reduced or discontinued if azotemia develops.
Congestive Heart Failure
Patients with mild heart failure may not have appreciable edema and diuretic therapy is not an absolute necessity, particularly if patients can restrict sodium intake. If hypertension coexists, it is sensible to employ a thiazide diuretic, which may be sufficient to control mild edema, if present. However, most patients with congestive heart failure will eventually develop edema to the extent that requires the use of a loop diuretic. Responsiveness to oral loop diuretics in patients with heart failure is dependent on several factors, including gastrointestinal absorption and tubular secretion. As long as renal function remains preserved, delivery of diuretic into the tubular fluid remains normal in heart failure. However, renal responsiveness to loops as measured by the natriuretic response to maximally effective doses can be one-third to one-fourth than that of healthy individuals. Larger doses will therefore not overcome this diminished response, unless renal insufficiency is present. Rather, the natriuretic response may be increased by giving moderate doses more frequently. In this manner, intravenous therapy is often 15appropriate in patients with severe heart failure or acute pulmonary edema. A thiazide diuretic can be added in combination to a loop diuretic in situations where the loop diuretic and sodium restriction are not adequate to control the edema. The synergy provided by such combinations can result in profound diuresis and patients must be followed closely to prevent severe hypokalemia and volume depletion to the extent that could induce circulatory collapse.
Nephrotic Syndrome
Diuretic resistance is often encountered in the nephrotic syndrome; a constellation of findings characterized by proteinuria, hypoalbuminemia, and generalized edema. As serum albumin concentrations are low, there is an increase in the permeability of the glomerular basement membrane to plasma proteins. The resulting decrease in plasma oncotic pressure alters Starling forces in the peripheral capillary beds, favoring fluid transudation into the interstitial compartment. Since diuretics are primarily bound to albumin, hypoalbuminemia also causes more diffusion of diuretic into the extracellular fluid, leading to reduction in delivery to the secretory sites and ultimately, the diuretic site of action. In severely hypoalbuminemic patients (<2 g/dL), coadministration of albumin with the loop diuretic (30 mg furosemide mixed with 25 g albumin) may increase the diuretic response. Doses of the loop diuretic must be sufficient not only to overcome urinary binding, but they must also be administered more frequently. Metolazone or another thiazide diuretic may be combined with the loop diuretic as an additional strategy in nephrotic patients.
❑ ADVERSE EFFECTS OF DIURETICS
A number of important and predictable adverse effects can occur with diuretics. Flowchart 1 illustrates some of the more commonly noted effects and the pathways by which they can occur. Both thiazide and loop diuretics increase potassium and magnesium excretion. On an average, potassium will fall by 0.3–0.4 mEq/L with typical dosing. The incidence of clinically relevant hypokalemia with thiazides is reduced when they are combined with ACE inhibitors or ARBs. Diuretic-induced hypokalemia can be managed by coadministering a potassium-sparing diuretic or oral potassium supplements. Potassium-sparing diuretics are generally more effective since they correct the underlying etiology and have the additional effect of reducing magnesium excretion. Maintenance of potassium homeostasis is important, since epidemiologic evidence implicates hypokalemia in the pathogenesis of diuretic dysglycemia and new-onset diabetes. It is important to recognize that new-onset diabetes will occur over time in many hypertensive patients regardless of type of antihypertensive used. Hyponatremia is often caused by diuretics. Several risk factors predispose patients to diuretic-induced hyponatremia, these include:
- Older age
- Female gender
- Psychogenic polydipsia and concurrent antidepressant use (in particular, selective serotonin reuptake inhibitors).
In the presence of these conditions, hyponatremia can occur at any time. Most patients are asymptomatic, but careful monitoring of serum sodium should occur as well as counseling patients to avoid excessive free-water intake in order to minimize risks of its occurrence. Diuretics can increase serum lipid levels, primarily total cholesterol and low-density lipoproteins, approximately 5–7% in the first year of therapy.16
However, these increases are short lived and the high prevalence of statin background therapy in hypertensive patients generally makes this an inconsequential finding. Few clinically relevant drug interactions occur with diuretics:
- As they compete with uric acid for secretion by the organic acid pathway, diuretics can increase serum uric acid and precipitate gout in some patients
- Nonsteroidal anti-inflammatory drugs can antagonize their therapeutic effects
- They can also increase the risk of hyperkalemia when combined with potassium-sparing agents
- Use of potassium-sparing diuretics with ACE-inhibitors or ARBs also entails an increased risk for hyperkalemia.
Other adverse effects of diuretics can include interstitial nephritis, ototoxicity (particularly with high-dose loop therapy), sun sensitivity, skin reactions, and uropathy. Contrary to popular belief, diuretics do not need to be avoided in patients with a history of allergy to sulfonamide-based antibiotics.
❑ SUMMARY
For over 50 years, diuretic therapy has remained an important component of the management plan for a variety of cardiovascular-related disorders, including hypertension and volume overload states, such as congestive heart failure, cirrhosis, chronic kidney disease, and the nephrotic syndrome. Few drugs in any class can boast of maintaining such prominence in therapy as when they were originally introduced. Mutual attention paid to the diuretic site of action as well as an underlying knowledge of renal physiology and the pathophysiology of the disease provide a context in which to apply diuretic pharmacology in a manner that enables reliable prediction of their therapeutic and adverse effects. Tailoring therapy to the disease and the individual patient in this manner insures that an effective diuresis can be achieved under a variety of circumstances.
❑ SUGGESTED READINGS
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288: 2981–97.
- Blood Pressure Lowering Treatment Trialists’ Collaboration. Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J. 2008;2:2669–80.
- Brater DC, Chennavasin P, Seiwell R. Furosemide in patients with heart failure: shift in dose-response curves. Clin Pharmacol Ther. 1980;28:182–6.
- Brater DC. Pharmacology of diuretics. Am J Med Sci. 2000;319:38–50.
- Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403–19.
- Carter BL, Ernst ME. Should diuretic therapy be first step therapy in all hypertensive patients? In: Toth PP. Sica DA (Eds). Clinical Challenges in Hypertension II, 1st edition. Atlas Medical Publishing; Oxford: 2010.
- Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527–35.
- Rasool A, Palevsky PM. Treatment of edematous disorders with diuretics. Am J Med Sci. 2000;319:25–37.
- Roos JC, Boer P, Koomans HA, et al. Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension. Eur J Clin Pharmacol. 1981;19:107–12.
- Wright JT, Probstfield JL, Cushman WC, et al. ALLHAT findings revisited in the context of subsequent analyses, other trials, and metaanalyses. Arch Intern Med. 2009;169: 832–42.
1.2 Vasodilators and Neurohormone Modulators
❑ INTRODUCTION
It has long been recognized that impedance to left ventricular (LV) outflow is a critical determinant of cardiac performance. This is especially true of patients with impaired LV systolic performance, such as in systolic heart failure (Fig. 4). Ultimately, the failing heart loses its natural ability to respond to increased impedance to ejection (i.e. loss of homeometric autoregulation), although lowering systemic resistance by drugs can rescue myocardial systolic function to some extent.
Heightened resistance or impedance to LV ejection is often referred to as “afterload”, but the term afterload originates from isolated muscle studies done in the mid-1970s and is not, strictly speaking, appropriately applied to the clinical setting. Afterload is defined as ventricular wall stress during shortening and cannot easily be measured in the intact circulation. Afterload is a product of LV cavity size (LaPlace relationship) and is inversely related to wall thickness or hypertrophy. In clinical practice, systemic vascular resistance (SVR) is frequently calculated [SVR = (mean arterial pressure – CVP) × 80/cardiac output] from right heart catheterization data, but this calculation is largely an estimate of small peripheral vessel caliber resistance. SVR is therefore only a part of the total impedance (Table 4) that the LV sees during ejection. Aortic impedance is also not typically measured as part of clinical care.
FIGURE 4: The relationship between various degrees of left ventricular dysfunction and afterload stress.(Source: Modified from Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure. N Engl J Med. 1977;297:27-31, 254–8, with permission)
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❑ VASODILATOR DRUGS AND LOW BLOOD PRESSURE
Patients with moderate-to-severe heart failure often have low blood pressure (BP) that is asymptomatic. Low brachial systolic pressure is sometimes perceived by physicians as a contraindication to the use of arteriolar dilator drugs, such as nitrates, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or carvedilol. However, vasodilator drugs can maintain or even increase systolic BP by increasing stroke volume in patients with systolic heart failure.
Arterial Versus Venous Effects of Vasodilator Drugs in Patients with Systolic Heart Failure
Arteriolar dilating drugs, such as hydralazine or amlodipine, reduce aortic impedance and thereby increase the velocity of shortening during LV ejection. LV end-systolic volume is thus reduced and LV ejection fraction increases. With hydralazine, LV end-diastolic volume (i.e. preload) may not acutely be altered, so the stroke volume response can be markedly increased. Essentially, the hemodynamic effects of vasodilator drugs are dependent on the relative effects of the drug on resistance and capacitance vessels. In patients with severe regurgitant lesions, such as mitral or aortic regurgitation, vasodilator drugs reduce the regurgitant fraction and increase forward cardiac output, thus adding to their beneficial effects.
The reflex tachycardia observed in normal subjects in response to arteriolar dilating drugs is not seen in patients with advanced systolic heart failure. This is likely due to the reduced cardiac norepinephrine spillover rate that occurs with unloading of the baroreceptors and low-pressure mechanoreceptors in response to systemic vasodilation in heart failure.
❑ ARTERIOLAR VASODILATORS
Hydralazine
Hydralazine is an old drug, one of the first to be used to treat hypertension in the 1950s. Its mechanism of action is still not completely elucidated, but it appears to be a direct acting, potent arteriolar dilator that relaxes the smooth muscles of small resistance vessels. It has essentially no venodilating effects. Hydralazine primarily dilates the renal- and peripheral-resistant arterioles and has little effect on coronary or liver blood flow. It may also have antioxidant effects and can prevent tolerance to nitrates.
Hydralazine can be given orally where it is rapidly absorbed from the gastrointestinal tract. However, the bioavailability is highly variable and depends on the rapidity that is acetylated by the liver, a genetically determined trait. In the United States, about half of the people are fast acetylators and half are slow acetylators. Acetylation activity is not routinely measured in patients.20
FIGURE 5: Mortality curves of African–American patients randomized to placebo or isosorbide dinitrate/hydralazine in addition to standard therapy for heart failure in the African–American Heart Failure Trial (A-HeFT).(Source: Modified from Taylor AL, Zliesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351:2049-57, with permission)
A lupus-like syndrome is more likely to occur in slow acetylators, and this typically wanes when hydralazine is stopped. Fast acetylators may require higher doses of hydralazine. Chronic hydralazine use can cause vitamin B6 deficiency.
The hemodynamic response to chronic oral hydralazine therapy in patients with systolic heart failure is usually characterized by no change in heart rate, a fall in SVR and about a 50% increase in cardiac output. Usually, BP does not change much. Patients with chronic mitral or aortic regurgitation demonstrate a reduction in the regurgitant jet by echo and auscultation, and forward stroke volume is markedly increased. There is no long-term improvement in exercise capacity despite a modest, persistent improvement in EF.
Due to the high success rate of other vasodilator drugs, such as ACE inhibitors and ARBs, hydralazine has been relegated to second-tier therapy. The one important exception is featured by the results of the African-American Heart Failure Trial (A-HeFT) (Fig. 5). In this trial, the combination of hydralazine and isosorbide dinitrate in a combination of fixed-dose drug added to standard therapy improved survival and other outcomes among black patients with systolic heart failure. The combination of hydralazine and isosorbide dinitrate today should be considered as an add-on therapy, superimposed on more conventional therapy, when patients are demonstrating signs and symptoms of worsening heart failure.
Amlodipine
Amlodipine is a dihydropyridine L-type calcium channel blocking agent that is widely used to treat hypertension and angina. It is a long-acting, potent, arteriolar dilating drug that is well tolerated. The typical starting dose is 2.5 or 5 mg/day and the target dose for many patients is 10 mg/day. Calcium channel drugs are vasodilators and have anti-ischemic effects, so it is logical that they would be investigated in patients with systolic heart failure.
Other nondihydropyridine calcium channel blockers, such as verapamil and diltiazem, may either have negative inotropic properties, cause cardiac electrical 21conduction problems or are simply not very powerful vasodilators. They do not play any role in the treatment of heart failure.
Oral Nitrates
Nitrates have been widely used to treat angina by physicians for well over 100 years. It is only in the past 25 years that they have been used to treat systolic heart failure. Their favorable effects on angina, systolic heart failure, mitral regurgitation and coronary spasm are now well known. Nitrates primarily cause venodilation, which typically increases capacitance and reduces preload, thus, lowering end-diastolic volume, reducing cardiac wall tension and diminishing PCWP. Dyspnea is relieved. Larger doses lead to arteriolar dilation, further reducing afterload and improving forward flow. LV cavity size diminishes, reducing mitral regurgitation. It is not surprising that oral nitrate therapy has emerged as an important treatment for systolic heart failure. Nitrates are among the few vasodilators that are able to increase exercise tolerance in patients with systolic heart failure. However, nitrate tolerance occurs in many patients (Fig. 6), thus casting suspicion on long-term efficiency. This can be offset to some extent by hydralazine.
FIGURE 6: The data indicate that tolerance can develop to intravenous nitroglycerin (NTG) over 24 hours. There is a brisk initial response to IV NTG manifested by a fall in pulmonary capillary wedge pressure (PCWP) during titration; but during 24 hours of infusion, PCWP increases back toward control in both the NTG and the placebo arms of the study.(Source: Modified from Elkayam U, Kulick D, Mclntosh N, et al. Incidence of early tolerance to hemodynamic effects of continuous infusion of NTG in patients with coronary artery disease and heart failure. Circulation. 1987;76:577-84, with permission)
❑ RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS) BLOCKERS
Angiotensin-converting Enzyme Inhibitors (ACE Inhibitors)
ACE inhibitors were introduced into clinical practice in the 1980s for the treatment of hypertension and heart failure. This class of drug therapy has revolutionized therapy for these two conditions and has been demonstrated to improve survival in patients with systolic heart failure. The development of this class of drugs for the treatment of heart failure was predicated on the observation that the RAAS is activated in chronic heart failure and contributes importantly to heightened afterload and to the LV remodeling process.
Angiotensinogen is produced in the liver and is converted in the blood by renin to form a small peptide, angiotensin I (Flowchart 2). Angiotensin I is then further cleaved to form angiotensin II, a very small peptide but potent arteriole constrictor. Angiotensin II subserves a host of other biological activities primarily through the angiotensin II receptor, including promotion of volume retention, activation of and sensitization to the sympathetic nervous system (SNS), thirst, regulation of salt and water balance, modulation of potassium balance, cardiac myocyte, and vascular smooth muscle growth, to name a few. Its actions are central to the development of acute and chronic systolic heart failure.
We now recognize that neurohormonal activation plays a key role in the initiation and progression of heart failure. The RAAS is central to this neurohormonal cascade, as patients with systolic heart failure and high renin levels seemingly derive the most acute benefit from blocking the RAAS. It is now well established that ACE inhibitors slow the progression of heart failure and improve survival in patients with a reduced ejection fraction and congestive heart failure. Much of this improvement is believed to be due to “reverse remodeling”.
It is now considered that systolic heart failure is at least in part driven by excessive neurohormonal activation, setting up a vicious cycle of worsening heart failure and death (Flowchart 3). Even though these neurohormonal systems are likely adaptive in an evolutionary sense, and are not simple biomarkers or epiphenomena, they are known to directly contribute to LV remodeling and even patient mortality. The strong notion emerged that pharmacological inhibition of the RAAS (and the SNS) might reduce the progression of LV remodeling, and therefore such drugs should improve patient survival.
ACE inhibitors have now become a standard of care for patients with:
- Hypertension
- Systolic heart failure
- Acute myocardial infarction
- Advanced cardiovascular disease.
Their role in the treatment of patients with systolic heart failure is now undoubted. The drugs acts through a variety of mechanisms:
- They reduce SVR, presumably by inhibiting angiotensin II arteriolar constriction reducing sympathetic tone There is also marked venodilation with a fall in PCWP, presumably due to reduction in sympathetic activity to veins and desensitization of venous capacitance vessels to norepinephrine
- Venous capacitance vessels dilate in response to ACE inhibitors due to reduced sympathetic activity at the neuroeffector level
- These drugs produce a modest improvement in cardiac index and the heart rate may be slightly slow.
FLOWCHART 2: The renin–angiotensin–aldosterone system(Source: from Kalidindi SR, Tang WH, Francis GS. Drug insight: Aldosterone-receptor antagonists in heart failure—The journey continues. Nat Clin Pract Cardiovasc Med. 2007;4(7):368-78, with permission)
(Abbreviations: ACE: Angiotensin-converting enzyme; ACEI: Angiotensin-converting enzyme inhibitor; ang I: Angiotensin I; ang II: Angiotensin II; AT: Angiotensin receptor; ET: Endothelin; NO: Nitric oxide; PAI: Plasminogen activator inhibitor; PGs: Prostaglandins; TIMP: Tissue inhibitor of metalloproteinase; tPA: Tissue plasminogen activator).
FLOWCHART 3: Heart failure is a complex clinical syndrome characterized by extensive neuroendocrine activation. The release of neurohormones appears to be in response to reduced cardiac function and a perceived reduction in effective circulatory volume. It is as if neuroendocrine activity is attempting to protect the blood pressure and maintain circulatory homeostasis. Although this may be adaptive early on, chronic neuroendocrine activation leads to peripheral vasoconstriction, left ventricular remodeling and worsening left ventricular performance, and thus becomes an attractive therapeutic target. Drugs designed to block the exuberant neuroendocrine response, such as ACE inhibitors, have now become the cornerstone of treatment for heart failure(Source: Francis GS, Tang WH. In: JD Hosenpud, BH Greenberg (Eds). Congestive Heart Failure, 3rd edition. Philadelphia: Lippincott Williams and Wilkins; 2007. pp. 602–19)
(Abbreviations: LV: Left ventricle; AVP: Arginine vasopressin; ANF: Atrial natriuretic factor; PRA: Plasma renin activity).
There is now a long list of ACE inhibitors to choose from Table 5 They have somewhat dissimilar pharmacodynamics, pharmacokinetics and rates of elimination. In general, it is best to start with small doses of ACE inhibitors and slowly titrate up over days to weeks to a target dose established as safe and effective by use in large clinical trials. It is expected that many patients with advanced systolic heart failure will have about a 20% increase in serum creatinine with ACE inhibitor use. This is usually not a reason to discontinue or lower the dose of the ACE inhibitor. Careful, regular follow-up with a check on electrolytes, blood urea nitrogen (BUN) and serum creatinine is important in the care of these patients when making decisions about altering the dose of ACE inhibitors.
Angiotensin Receptor Blockers (ARBs)
Angiotensin receptors of the AT1 subtype bind angiotensin II with a high structural specificity but limited binding capacity. The remarkable success of ACE inhibitors in the treatment of hypertension, arterial disease, myocardial hypertrophy, heart failure, and diabetic renal disease encouraged the development of alternative drugs to block the RAAS. It was eventually recognized that ACE inhibitor drugs blocked only one of several pathways that reduces angiotensin II activity, and that angiotensin II could “escape” from chronic ACE inhibition. ARBs do not demonstrate this “escape” phenomenon. ARBs do not cause cough.25
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They can be used safely in patients who develop angioedema during treatment with an ACE inhibitor. The incidence of renal dysfunction and hyperkalemia is comparable with ARBs and ACE inhibitors. It is now reasonably clear that ACE inhibitors and ARBs should not be used together, as the likelihood of hyperkalemia, hypotension, and worsening renal function is greater.
Several important points have emerged from many large trials:
- ARBs and ACE inhibitors appear to have very similar efficiency in these patient groups
- If the patient does not tolerate an ACE inhibitor, an ARB is a suitable substitution
- Although generally more expensive, ARBs are better tolerated than ACE inhibitors
- The combination of an ACE inhibitor and an ARB (dual RAAS blocking effect) does not lead to more efficiency and is associated with more hypotension, worsening renal function and hyperkalemia. Despite earlier favorable reports, ARBs do not appear to prevent recurrent atrial fibrillation.
The dose of ARBs has generally been determined by pharmaceutical-generated data and subsequent verification of these doses in large clinical trials (Table 5).
❑ MINERALOCORTICOID (ALDOSTERONE) RECEPTOR BLOCKERS
Aldosterone and Systolic Heart Failure
Aldosterone was structurally identified more than 50 years ago and was soon after designated as mineralocorticoid due to its salt-retaining properties. It also releases potassium from the kidney, gastrointestinal tract, sweat, and salivary glands. It has long been known to play a pathophysiologic role in cardiovascular disease, including congestive heart failure (Flowchart 4). In addition to its mineralocorticoid properties, which can cause hypokalemia and hypomagnesemia, aldosterone contributes in many ways to the development of heart failure.
Inhibition of aldosterone is believed to be favorable due to:
- Reduced collagen deposition and possibly antiremodeling effects
- Reduction in BP
- Prevention of hypokalemia and associated arrhythmias
- Modulation of nitric oxide synthesis (Flowchart 4).
The major mineralocorticoid in heart failure is cortisol and not aldosterone. Serum aldosterone levels are not consistently elevated in patients with heart failure in the absence of diuretics. Accordingly, it is not aldosterone blockade per se, but mineralocorticoid receptor blockade that is important. Spironolactone and eplerenone are thus mineralocorticoid receptor blockers more than simply aldosterone receptor blockers.
There is now much greater interest in studying aldosterone receptor blockers. Two landmark studies, the randomized aldosterone evaluation study (RALES) and the myocardial infarction heart failure efficacy and survival study (EPHESUS) have remarkably increased the role of aldosterone mineralocorticoid antagonists for the everyday treatment of systolic heart failure. The drugs spironolactone and eplerenone are now widely used to treat chronic systolic heart failure and post-myocardial infarction heart failure.
Spironolactone and Eplerenone in Chronic Heart Failure
The mechanism of action of spironolactone is complex, as aldosterone mineralocorticoid modulates many features of the heart failure syndrome.27
FLOWCHART 4: Aldosterone is a mineralocorticoid that has a central role in a host of biological activities. Many of these activities can be excessive due to dysregulation of aldosterone activity, thus contributing to cardiovascular disease(Source: Modified from Struthers AD, MacDonald TM. Review of aldosterone and angiotensin-II-induced target organ damage and prevention. Cardiovasc Res. 2004;61:663-70, with permission)
(Abbreviations: LVH: Left ventricular hypertrophy; PAI-1: Plasminogen activator inhibitor-1).
Patients taking spironolactone need to be frequently and carefully monitored, as hyperkalemia and azotemia can occur with spironolactone, particularly if nonsteroidal anti-inflammatory drugs are used concomitantly.
With the results of RALES trial in 1999, it was clearly demonstrated that spironolactone (25–50 mg per day) added to standard therapy (b -blockers were not yet in widespread use) was safe and reduced mortality by 30%. Death from progressive heart failure and sudden death were both reduced by spironolactone. The patients who participated in RALES were primarily NYHA class III (70%) and IV (30%).
Eplerenone, a newer, more selective aldosterone mineralocorticoid receptor blocker, causes less gynecomastia and breast tenderness than spironolactone. It is more mineralocorticoid specific than spironolactone. EPHESUS was conducted in patients who experienced a recent acute myocardial infarction with an EF of 40% or less who had heart failure, or had a history of diabetes mellitus. Eplerenone (average dose 42.6 mg per day) reduced all-cause mortality by 15%, cardiovascular mortality by 17% and significantly lowered the need for subsequent hospitalization.
The EMPHASIS-HF trial (Effect of Eplerenone versus Placebo on Cardiovascular Mortality and Heart Failure Hospitalization in Subjects with NYHA Class II Chronic Systolic Heart Failure) which employed eplerenone in a large double-blinded trial of patients with more mild (NYHA class II) heart failure was recently stopped prematurely when a favorable response was noted.28
❑ PHOSPHODIESTERASE TYPE 5 INHIBITORS
Sildenafil and Tadalafil
Phosphodiesterases are enzymes that hydrolyze the cyclic nucleotides—c-GMP and cyclic adenosine monophosphate (cAMP). Phosphodiesterase 5 (PDE 5) degrades c-GMP via hydrolysis, thus influencing c-GMP's ability to modulate smooth muscle tone, particularly in the venous system of the penile corpus cavernosum and in the pulmonary vasculature.
Sildenafil and tadalafil are useful in patients with pulmonary arterial hypertension who have mild-to-moderately severe symptoms. Preliminary data on sildenafil suggest that its use may also be safe and even beneficial in patients with disproportionate pulmonary hypertension and LV dysfunction. Sildenafil citrate is prescribed in doses of 20 mg TID and tadalafil is much longer acting and is prescribed in doses of 5 mg per day as needed to control pulmonary hypertension. Hypotension can occur with PDE 5 inhibitors, especially when they are used with nitrates.
❑ INTRAVENOUS VASODILATORS
Nitroprusside
Sodium nitroprusside can be dramatic in reversing the deleterious hemodynamics of acute systolic heart failure. Those who have had experience using the drug in this setting are often astonished how quickly the drug lowers PCWP and improves cardiac output, leading to prompt and often striking clinic improvement. The drug is usually started as doses of 10 mcg/min, and gradually titrated up to not more than 400 mcg/min, as needed to control hemodynamic abnormalities and symptoms.
Metabolism and Toxicity of Nitroprusside
Nitroprusside has been used to treat severe heart failure for many years, although the Food and Drug Administration (FDA) has approved it only for severe hypertension and hypotensive surgery. Thiocyanate toxicity can occur, and thiocyanate levels should be checked as needed. Measurement of thiocyanate is a simple, inexpensive colorimetric test, normal levels being less than 10 mg/mL. Metabolic acidosis, anuria, and a prolonged high dose of nitroprusside (>400 mcg/min) can predispose to thiocyanate toxicity, prompting the measurement of thiocyanate levels.
Nitroprusside and Severe Heart Failure
Nitroprusside quickly improves hemodynamics and symptoms in patients with severe heart failure. Even patients with hypotension and shock may improve with nitroprusside, as BP may stabilize or even improve with a large increase in cardiac output. Patients with severe mitral regurgitations or aortic regurgitation may also demonstrate dramatic reversal of serious hemodynamic perturbations with nitroprusside. Patients with severe aortic stenosis and worsening heart failure can be improved with nitroprusside used prior to aortic value replacement, provided they are not hypotensive. It can also be used to stabilize acute heart failure in patients who demonstrate a ruptured interventricular septum following acute myocardial infarction. Recent data indicate that in patients hospitalized with advanced, low-output heart failure, those stabilized in the hospital with nitroprusside may have a more favorable long-term clinical outcome.29
Intravenous Nitroglycerin
Similar to nitroprusside, intravenous nitroglycerin has an immediate onset and offset of action. The infusion rate is usually initiated at 10–20 mcg/min and titrated slowly to 200–500 mcg/min as needed to control symptoms and improve hemodynamic parameters. It is not approved by the FDA for the treatment of heart failure but has been widely used for this indication over the past 20 years. Intravenous nitroglycerin is endothelium dependent, and unlike nitroprusside, it has more effect on the venous circulation than on the arterial circulation. However, higher doses of intravenous nitroglycerin decrease SVR, as well as increase venous capacity. Therefore, cardiac output increases and BP can be maintained. PCWP is reduced. Mitral regurgitation improves. There are few data available on the effects of intravenous nitroglycerin on coronary circulation in patients with heart failure. Coronary blood flow appears to improve. This suggests that both the epicardial conductance vessels and the coronary arteriolar resistance vessels are favorably influenced by intravenous nitroglycerin.
Nesiritide
Nesiritide is pure human brain natriuretic peptide (BNP), synthesized using recombinant DNA techniques. It has the same 32-amino acid sequence as endogenous BNP released from the heart. When infused intravenously into the circulation of patients with heart failure, the mean terminal elimination half-life of nesiritide is about 18 minutes. Plasma BNP levels increase about threefold to sixfold with nesiritide infusion.
The largest clinical trial of nesiritide, Vasodilation in the Management of Acute CHF (VMAC), was a comparison study with intravenous nitroglycerin. It demonstrated that nesiritide improved hemodynamic function and self-reported symptoms are more effective than intravenous nitroglycerin or placebo (Figs 7A and B). On this basis, nesiritide was approved by the FDA for heart failure and became widely used for the treatment of acute heart failure. Nesiritide has venous, arterial, and coronary vasodilator properties. Cardiac output improves and PCWP reduces. Hypotension occurs in about 4% of patients, and unlike intravenous nitroglycerin, it can be prolonged (~20 min) because of nesiritide's relatively longer half-life. The effects of nesiritide on renal function are variable, but generally only a modest or neutral renal effect is observed, though worsening renal function has been reported.
❑ ORAL β -ADRENERGIC BLOCKING DRUGS
There is a fundamental belief that the biologically powerful adrenergic nervous system compensates the failing heart by increasing myocyte size (hypertrophy), heart rate and force of contraction (inotropy). The SNS also activates the RAAS, thus conserving intravascular volume and redirecting blood flow to vital organs. However, an overly active SNS has repeatedly been shown to be essentially toxic to myocardial cells in both animals and humans. There have been numerous large randomized trials supporting the concept that blocking the SNS with β -adrenergic blocking drugs in patients with systolic heart failure slows the progression of systolic heart failure and improves patient survival.
It is well known that β -adrenergic receptors downregulate in response to excessive sympathetic drive, presumably in an attempt to protect the cardiac myocyte from overstimulation. Such biological behavior suggests that blocking the receptors pharmacologically may also protect the heart.30
FIGURES 7A AND B: Changes in pulmonary capillary wedge pressure from baseline in response to intravenous nitroglycerin, nesiritide and placebo in patients with heart failure(Source: Modified from Publication Committee for the VMAC Investigators (Vasodilatation in the management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA.2002;287:1531-40, with permission)
β -adrenergic blocking drugs are now widely used to treat all stages of heart failure. Some patients admitted to the hospital with NYHA class III or IV systolic heart failure may not tolerate β -blockers, because of symptomatic hypotension or low cardiac output. The continuation of β -blocker therapy in patients hospitalized with acute decompensated systolic heart failure is associated with lower postdischarge mortality risk and improved treatment rates.
Although it is unusual nowadays to see patients with heart failure who are naive to either RAAS blockers or β -blockers, occasionally the issue of which class of drug to start first arises. We now have three major heart failure therapeutic strategies aimed at producing reverse remodeling:
- RAAS blocking drugs
- Cardiac resynchronization therapy (CRT)
- β -adrenergic blocking drugs.
Of course, coronary revascularization can also improve LV size and performance in selected patients. These therapies have proven to be the powerful drivers of improved patient survival.
❑ CONCLUSION
Neurohumoral modulating drugs now have a central role in the treatment of patients with systolic heart failure. This was not the case 35 years ago when only digitalis and diuretics were used. Annualized mortality has fallen from ~20% to less than 10% per year commensurate with the use of RAAS and SNS blocking drugs. Of course, ICDs and CRT have also importantly contributed to this mortality reduction. The total cardiovascular death rate burden has fallen substantially in accordance with the widespread use of these therapies. Although, the incidence of ST segment elevation myocardial infarction (STEMI) has also fallen dramatically, incident heart failure continues to increase. There is now much better treatment for hypertension and hyperlipidemia. Paradoxically, as people live longer, we are now seeing a wave of heart failure in the elderly, the fastest growing segment of our population. The scourge of heart failure has not gone away but has rather been shifted to people in their 70s, 80s and 90s. In the end, prevention of heart failure by lifelong control of known risk factors and mechanistic enlightenment, although additional genomic studies may reduce the burden of heart failures even more, as systolic heart failure is likely a largely preventable disorder.
❑ SUGGESTED READINGS
- Anand IS, Tam SW, Rector TS, et al. Influence of blood pressure on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine in the African-American Heart Failure Trial. J Am Coll Cardiol. 2007;4932–9.
- Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355:637–45.
- CIBIS Investigators and Committees. A randomized trial of?? blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;90:1765–73.
- CIBIS-II Investigator and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet. 1999;353:9–13.
- Cohn JN. Structural basis for heart failure. Ventricular remodelling and its pharmacological inhibition.
- GISSI- AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360:1606–17.
- Guiha NH, Cohn JN, Mikulic E, et al. Treatment of refractory heart failure with infusion of nitroprusside. N Engl J Med. 1974; 291:587–92.
- ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–59.
- Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–9.
- The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325:293–302.
- VMAC. Intravenous nesiritide vs nitroglycerin for treatment ofdecompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531–40.
- Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection trials. Circulation. 2004;110:2618–26.
1.3 Positive Inotropic Drugs
❑ INTRODUCTION
Positive inotropic drugs (also know as positive inotropes) are agents that increase the velocity and strength of contraction of the cardiac myocyte and as a consequence, the myocardium and the heart as an organ unit; a few of the measurements of contractility or inotropy include δ LV systolic upstroke pressure/δ time, peak slope of LV developed pressure and end-systolic elastance. Positive inotropic drugs are, therefore, generally directed at patients whose overall cardiovascular function is compromised by loss of cardiac contractility resulting in symptoms and signs of depressed stroke volume, cardiac output, hypoperfusion of vital organs and systems and often, hypotension. In general, positive inotropes enhance cardiac contractility via modulation of calcium handling by the cardiomyocyte. The cellular mechanisms of action of the major inotropic drugs are illustrated in Figure 8.
❑ INTRAVENOUSLY ADMINISTERED, SHORT-TERM POSITIVE INOTROPIC THERAPY
The agents under this heading represent a spectrum of pharmacologic properties in addition to their positive inotropic effects. The predominant distinguishing feature among these agents is their effect on vasculature, which can range from vasodilatation to balanced vascular tone to vasoconstriction (Fig. 9 and Table 6). The pharmacologic mechanisms for their positive inotropy on increasing intracellular cyclic adenosine monophosphate (cAMP) by either adrenergic receptor stimulation or inhibition of cAMP degradation (Fig. 8).
Adrenergic Receptor Agonists
Although the adrenergic agonists can evoke tachycardia and dysrhythmias, they do have short elimination half-lives, an ideal pharmacologic property in the monitored critical care setting where a quick “turn on” and “turn off” of cardiovascular effects allow immediate and tightly controlled hemodynamic support.
The catechols (3,4-hydroxyphenyl ring) are the major drug group in the adrenergic family used for positive inotropic therapy. The cardiovascular effects of adrenergic agents used clinically for inotropic and hemodynamic support are individually presented under the heading of each and summarized in Table 6.33
FIGURE 8: The major positive inotropic groups generally act through mechanisms that increase the concentration and availability of intracellular calcium for the actin–myosin contractile apparatus. Beta-adrenergic agonists attach to the beta-adrenergic receptor, activating the Gs protein adenylate cyclase complex to convert ATP to cAMP. cAMP activates protein kinase A, which phosphorylates several intracellular sites resulting in an influx and release of Ca++ for systole. Phosphodiesterase inhibitors retard the breakdown of cAMP. Calcium sensitizers act by making the troponin–actin–myosin complex more responsive to available Ca++. By blocking the Na/K ATPase pump, digoxin increases intracellular Na+ loading of the Na+-Ca++ exchanger, resulting in less extrusion of Ca++ from the myocyte. Dashed arrow indicates inhibition. While this illustration depicts the major pharmacologic actions of these positive inotropic groups, their comprehensive mechanisms are considerably more numerous and complex. (Abbreviations: ATP: Adenosine triphosphate; cAMP: Cyclic adenosine monophosphate; AMP: Adenosine monophosphate; PDE: Phosphodiesterase; BAR: Beta-adrenergic receptor; PKA: Protein kinase A)
FIGURE 9: The spectrum of net vascular properties of the agents currently available for short-term positive inotropy and cardiovascular support. The vascular effects and responses are a major determinant for selection in individual patients
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Dobutamine
Dobutamine is the agent most commonly used for short-term intravenous inotropic support, and its net cardiovascular effects in the setting of left ventricular systolic failure result predominantly from positive inotropic enhancement of depressed cardiac contractility. Dobutamine was developed from methodical manipulation and substitutions on the basic catechol-phenylethylamine molecule.
The major clinical indication for dobutamine administration is short-term inotropic support in patients compromised by ventricular systolic dysfunction, which has resulted in a problematic reduction in blood pressure and systemic perfusion (Table 7).
In the appropriate patient, namely the patient with ventricular systolic dysfunction resulting in a fall in stroke volume and cardiac output, an elevation in left ventricular end-diastolic filling pressure, systemic hypoperfusion and mild-to-moderate reduction in systemic blood pressure, dobutamine increases stroke volume, cardiac output, systemic systolic blood pressure and pulse pressure, and systemic perfusion, while decreasing pulmonary and systemic vascular resistance and left ventricular filling pressure.
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While there appears to be a dose-related separation of positive inotropy and beneficial hemodynamic effects from positive chronotropy, higher dosing will evoke a faster heart rate and can provoke ectopic beats and tachydysrhythmias.
Dobutamine can be safely administered to heart failure patients with occlusive coronary disease to attain and maintain a stable clinical and hemodynamic short-term course until the patient is directed to more advanced management (e.g. intra-aortic balloon counterpulsation, coronary angiography and intervention, coronary bypass surgery). Dobutamine may have a favorable effect on myocardial stunning beyond the simple increase in coronary blood flow and myocardial perfusion of the affected region or whole heart.
The most common clinical scenarios for appropriate dobutamine administration (to improve and stabilize hemodynamic and clinical status) include patients managed for:
- Decompensated, hypoperfused, often hypotensive chronic systolic heart failure
- Acute systolic heart failure (e.g. acute myocardial infarction, acute myocarditis)
- Immediately following cardiac surgery + cardiopulmonary bypass.
The various considerations for the administration of dobutamine are presented in Table 7.
Although the usual dose range for dobutamine is 2.0–15.0 mcg/kg/min, many patients can experience clinical and hemodynamic benefit at a lower starting dose of 0.5–1.0 mcg/kg/min and do so with minimal to no increase in heart rate or dysrhythmias. Dosing can be advanced by 1.0–2.0 mcg/kg/min increments every 12–15 or more minutes until the desired clinical and hemodynamic effects are attained. When discontinuing, maintenance doses of less than or equal to 2.0 mcg/kg/min can usually be stopped without difficulty. Higher infusion rates over an extended period generally require weaning over 12–72 hours to avert clinical and hemodynamic deterioration with more abrupt discontinuation.
The pharmacokinetic and pharmacodynamic properties of dobutamine endorse its application as a short-term positive inotropic agent. Most of the drug is eliminated within 12–13 minutes upon discontinuation of the infusion, allowing a rapid dissipation of adverse effects if encountered during the infusion. In human heart failure, there is a direct near-linear relationship between the infusion dose of dobutamine, its plasma levels, and hemodynamic responses.
Adverse effects are largely attributable to its administration in a more ill and compromised patient or due to improper patient and/or dose selection. The most common adverse effects of dobutamine are tachycardia and dysrhythmias. Other side effects, also generally dose related, include headache, tremor, anxiety, palpitations, and nausea. A hypertensive response (elevated systemic systolic blood pressure) can be observed when dobutamine is administered to patients with a history of systemic hypertension or peripheral vascular disease. Patients with high-grade occlusive coronary artery disease can experience angina, myocardial ischemia and infarction, particularly in patients who do not meet the primary indication for use (Table 7) and/or receive excessive initial dosing or excessively rapid advancement of dose. Dobutamine infusions can lower plasma potassium concentrations.
Dopamine
While dopamine, an endogenous precursor of epinephrine and norepinephrine, is the simplest molecule of the adrenergic agents, it has the most complex 37pharmacology (Fig. 9 and Table 6). In general, dopamine elicits its pharmacodynamic effects through stimulation of dopaminergic receptors (D1 and D2) and adrenergic receptors (β1, β 2 and α) and through the neuronal release and reduced neuronal uptake of endogenous norepinephrine. At lower infusion rates (<4.0 mcg/kg/min) in human heart failure, dopamine behaves as a mild vasodilator (dopaminergic), particularly of visceral and renal arterial–arteriolar vascular beds. With increased dosing, this effect is overtaken by dopamine's agonism of adrenergic receptors directly and through its release of norepinephrine from nerve endings; vasodilatation gives way to a net-balanced vascular effect and some positive inotropy at moderate dosing (4.0–8.0 mcg/kg/min) and to considerable vasoconstriction and some retained inotropy at higher doses (>8.0 mcg/kg/min).
In states of low cardiac output, systemic hypoperfusion, and adequate or elevated left ventricular filling pressures, dopamine at less than 4.0 mcg/kg/min can augment ventricular contractility, stroke volume and cardiac output, and reduce systemic and pulmonary vascular resistance; all to a modest degree without a substantial change in systemic blood pressure. As infusion rates move to more than 4.0 mcg/kg/min, vascular resistance, stroke volume and cardiac output plateau and there occurs a substantial dose-related rise in systemic blood pressure. Positive chronotropy and provocation of dysrhythmias are also dose related and can become an undesirable effect at more than or equal to 6.0 mcg/kg/min. Indices of ventricular contractility (positive inotropy) are blunted at higher dosing and during continuous infusion, presumably secondary to the rise in blood pressure, vascular resistance and ventricular afterload and depletion of myocardial norepinephrine stores from dopamine-induced release (and reduced uptake) at nerve endings during high-dose or prolonged infusions.
The most common adverse effects of dopamine administration are similar to those of dobutamine, namely positive chronotropy and dysrhythmias, both dose related. Dopamine crosses the blood–brain barrier to provoke nausea and vomiting in some patients. Intense vasoconstriction by dopamine can lead to ischemia of digits and various organ systems. Subcutaneous infiltration at the infusion site can provoke pain and ischemic changes, potentially reversible with local instillation of phentolamine. Dopamine has been reported to depress minute ventilation in heart failure.
Other Adrenergic Agents
These agents are used in various clinical settings for various indications. Due to overriding vascular effects, they are not employed as primary positive inotropic drugs.
Isoproterenol: This drug is perhaps the purest beta-adrenergic receptor agonist (β 1 and β 2) available for clinical use. However, its positive inotropic properties are largely overshadowed by strong vasodilatory and positive chronotropic effects (Table 6). Its principal clinical application is rather narrow, namely to increase heart rate in the short-term (until recovery or definitive intervention) in patients with problematic bradycardia or inadequate heart rate response; particularly in clinical situations where intravenous atropine is contraindicated, inadequate, or ineffective. In view of other available, generally safer vasodilating agents (e.g. milrinone, nesiritide, nitrates), isoproterenol is rarely used as a primary vasodilating agent. Adverse effects include flushing, tremor, anxiety, tachycardia, dysrhythmias, and hypotension.38
Epinephrine: endogenous catecholamine stimulates β 1, β 2 and α 1 adrenergic receptors. Epinephrine differs from dobutamine in that its administration is modulated by neuronal uptake and its β 2 and α 1 effects are more intense than those of dobutamine. In cardiovascular medicine, epinephrine is most often employed during cardiopulmonary resuscitation or as a global hemodynamic support drug during withdrawal for cardiopulmonary bypass and recovery from cardiac surgery. Adverse effects include those described above for dobutamine, dopamine, and isoproterenol.
Norepinephrine and phenylephrine: agents are predominant α 1-adrenergic agonists with mild beta-receptor agonism, and thus, they are viewed as vasopressors (Fig. 9 and Table 6). As such, these compounds are used for vasoconstriction to increase and stabilize systemic blood pressure in states of marked hypotension and shock (vasodilatory and cardiogenic).
Norepinephrine dosing in hypotension and shock generally ranges 0.02–0.40 mcg/kg/min. In addition to the adverse effects described for dopamine, norepinephrine can evoke dose-related systemic hypertension and bradycardia. More intense vasoconstriction with minimal positive inotropy is rendered by phenylephrine.
Phosphodiesterase Inhibitors
Drugs under this grouping are often referred to as “inodilators” because vasodilation is a major component of their pharmacology. In fact, amrinone, studied early in this category, is principally a vasodilator with little to no ability to augment ventricular contraction beyond its unloading effects on the ventricle. Thrombocytopenia during prolonged administration tempered its clinical application. As a therapeutic modality, amrinone has largely been replaced by milrinone.
Milrinone
While milrinone can elicit some positive inotropy through other cellular mechanisms (e.g. activation of the calcium release channel), its cardiovascular effects are principally rendered through inhibition of phosphodiesterase III (PDE III) with consequent impairment of the breakdown metabolism of cAMP (Fig. 8).
In contrast to dobutamine, a positive inotrope with mild vasodilating properties, milrinone is a vasodilator with mild positive inotropic properties. Therefore, for any matched degree of enhanced contractility, milrinone evokes a greater reduction in pulmonary and systemic vascular resistance, systemic blood pressure, and ventricular filling pressures.
In patients with severe low output congestive heart failure, milrinone augments the hemodynamic effects of dobutamine and vice versa. It is not unusual to employ this combination in patients with markedly compromised hemodynamics, generally in the setting of advanced, end-stage heart failure, as a pharmacologic bridge to placement of a ventricular assist device and/or cardiac transplantation.
Milrinone is generally started at 0.20–0.30 mcg/kg/min and gradually advanced as needed to achieve the intended hemodynamic and clinical endpoints and short of evoking tachycardia, dysrhythmias or hypotension. Milrinone has a half-life of 1–3 hours, and thus, the onset of action and equilibration is not as prompt as that seen with the catechol inotropes. The lengthy elimination half-life (1–3 hours) results in a more prolonged recovery from adverse effects, once milrinone is discontinued.39
Other Intravenously Administered Positive Inotropic Interventions
A number of additional pharmacologic interventions are known to enhance myocardial contractility.
Calcium Sensitizers
Calcium sensitizers (e.g. levosimendan) augment cardiac contractility by modulating intracellular mechanisms of contraction at the same concentrations of intracellular calcium (Fig. 8).
Levosimendan: some of its positive inotropic effect is probably rendered through phosphodiesterase inhibition, levosimendan is reported to enhance myocardial contractility through sensitization of the contractile apparatus to available calcium by increasing or stabilizing calcium binding to troponin C.
Levosimendan behaves as an inodilator in human heart failure; it reduces vascular resistance and ventricular filling pressures, and augments stroke volume and cardiac output. Due to its prominent vasodilating properties, levosimendan should not be considered a first-line drug for low output hypotension or shock. Levosimendan itself has an elimination half-life of 1–2 hours, but a primary active metabolite (OR-1896) has a half-life of more than 75 hours.
Orally Administered Positive Inotropic Agents
Oral inotropes have not fared well over the past two decades as intervention to improve myocardial contractility and performance. While digitalis (currently digoxin) has been used for over 200 years to treat cardiac failure and “dropsy”, this coveted role has been reined in by the Digitalis Investigation Group (DIG) trial published in 1997. Many orally administered, non-digitalis agents have been formulated over the past four decades to replace digoxin in the therapeutics of human heart failure; examples include amrinone, milrinone, vesnarinone, pimobendan and butopamine; all were found to be ineffective, to provoke undesirable effects or to adversely affect outcomes.
Digitalis–Digoxin
Most of the enhancement of myocardial contractility by digoxin appears to be generated by inhibiting the Na+/K+ATPase pump of the cardiomyocyte sarcolemma (Fig. 8). This inhibition results in elevation of intracellular sodium, which increases (via blunting of the sodium–calcium exchanger) the intracellular calcium available for contraction. Digitalis may also direct calcium into the myocyte via modulation of the voltage-sensitive sodium channels.
Some of the clinical benefits of digitalis therapy in heart failure likely occur through alteration of sympathetic tone. Heart failure increases sympathetic nervous system tone and reduces parasympathetic tone, resulting in a number of undesirable effects, including increased vascular resistance, tachycardia, renin release and diminished baroreceptor sensitivity; many of these undesirable responses are favorably suppressed or reversed by chronic digitalis administration.
Intravenously administered digoxin in heart failure evokes a modest increase in mean stroke volume, cardiac output and systemic blood pressure, a modest decrease in heart rate and ventricular filling pressures, and little change in vascular resistance; although individual responses can vary widely with better hemodynamic effects noted in the more hemodynamically compromised patients.40
The DIG trial has overshadowed all prior studies regarding the use of digitalis chronically in patients with heart failure and sinus rhythm, and has now provided the framework for current digoxin use. Patients were randomized 1:1 to digoxin (median dose 0.25 mg/day) or placebo. Chronic digoxin therapy in the DIG Trial had no effect on total mortality but tended to reduce mortality attributable to heart failure and statistically reduced the combined endpoints of heart failure mortality or hospitalization for heart failure. While this benefit was greatest in patients with lower ejection fractions and worse clinical status, modest improvement was also noted for patients with an LV ejection fraction more than 0.45.
For the overall heart failure population, long-term digoxin administration has a Class IIa indication (level of evidence: B) from the 2009 ACC/AHA Task Force, which stated, “Digitalis can be beneficial in patients with current or prior symptoms of heart failure and reduced left ventricular ejection fraction to decrease hospitalizations in heart failure”. Chronic digoxin therapy remains an option to control ventricular rate in the heart failure patient with atrial fibrillation, although this consideration has been challenged. The initial and maintenance oral dose is 0.0625–0.25 mg/day. The 0.125 mg/day dose has largely replaced 0.25 mg/day as the standard maintenance dose because at the lower dose, serum digoxin levels (drawn >8 hours after dosing) typically remain less than or equal to 1.0 ng/mL in patients with normal renal function and clearance. Dose reduction or discontinuation becomes important in patients with renal dysfunction and/or during concomitant administration of medications known to elevate digoxin concentrations (Table 8).
Digoxin's direct effect on sinoatrial and atrioventricular nodal cells and its autonomic properties (reducing sympathetic tone and enhancing parasympathetic tone) leads to many of the manifestations of digoxin toxicity, generally at serum levels more than 2.0 ng/mL, including sinus bradycardia and AV nodal blockade.
Other Orally Administered Positive Inotropic Agents
Hydralazine has positive inotropic properties in human heart failure in addition to its well-established vasodilating, ventricular unloading effects.
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These inotropic and hemodynamic effects can be employed to wean dobutamine (and perhaps, milrinone and low-dose dopamine) from heart failure patients who appear hemodynamically dependent on the intravenous inotrope.
Absolute and relative hypothyroidism can play a major role in the clinical course and outcomes in heart failure. Thyroid hormone replacement enhances myocardial contractility through a number of mechanisms and is of particular clinical importance in these specific patient groups. Whether thyroid hormone intervention merits consideration as a means of augmenting cardiac performance and clinical outcomes in patients with heart failure beyond these groups remains unanswered.
❑ SUGGESTED READINGS
- Abraham WT, Adams KF, Fonarow GC, et al. In hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the acute decompensated heart failure national registry (ADHERE). J Am Coll Cardiol. 2005;46:57–64.
- Bristow MR, Ginsburg R, Umans V, et al. B1- and B2-adrenergic–receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective B1-receptor downregulation in heart failure. Circ Res. 1986;59:297–309.
- Burger AJ, Horton DP, LeJemtel TH, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. Am Heart J. 2002;144:1102–8.
- Gheorghiade M, Stough WG, Adams K, et al. The pilot randomized study of nesiritide versus dobutamine in heart failure (PRESERVDHF). Am J Cardiol. 2005;96(6A):18G–25G.
- Jessup M, Abraham WT, Casey DE, et al. 2009 Focused Update: ACCF/AHA Guidelines for the diagnosis and management of heart failure in adults. Circulation. 2009;119:1977–2016.
- Leier CV, Heban PF, Huss P, et al. Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation. 1978;58:466–75.
- Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting- enzyme inhibitors. RADIANCE study. N Engl J Med. 1993;329:1–7.
- The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–33.
- Tuttle RR, Mills J. Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circ Res. 1975;36185– 96.
1.4 Antilipid Agents
❑ INTRODUCTION
Over 150 years ago, Virchow and his colleagues described the accumulation of lipid as the hallmark of the atherosclerotic plaque. Since then, an extensive body of evidence has shown a direct relationship between blood cholesterol levels and atherosclerotic cardiovascular diseases. The large majority of clinical data come from statin trials. Other lipid modifying drugs have demonstrated more modest cardiovascular benefits.42
❑ APPROPRIATE USES
The National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) has identified two lipid targets for the prevention of cardiovascular diseases, LDL-C and non-high density lipoprotein cholesterol (non-HDL-C) (Table 9). The first target of therapy is LDL-C, with treatment goals based on the risk of a coronary heart disease event in the next 10 years. The second target of therapy is non-HDL-C Non-HDL-C is calculated by subtracting HDL-C from total cholesterol and reflects circulating levels of atherogenic apolipoprotein-B containing lipoproteins. The non-HDL-C goal is 30 mg/dL higher than the LDL-C goal.
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Although the NCEP ATP III guidelines recommended using non-HDL-C when triglycerides are 150–500 mg/dL, recent evidence suggests that this recommendation can be simplified to using the non-HDL-C goal when triglycerides are less than 500 mg/dL.
In those with triglyceride levels more than 500 mg/dL, prevention of pancreatitis is the initial objective. Once triglycerides are less than 500 mg/dL, attention can then turn to addressing LDL-C and non-HDL-C levels for cardiovascular prevention. Although low levels of HDL-C and high levels of triglycerides are markers of increased cardiovascular risk, specific treatment targets have not been identified due to the lack of evidence that pharmacologically altering the levels of these two factors per se reduces cardiovascular risk. Cardiovascular prevention efforts in patients with low HDL-C should focus on lifestyle and drug therapy to achieve LDL-C and non-HDL-C goals. In the NCEP ATP III 2004 update, statins were recommended as first line therapy for cardiovascular prevention.
Similar treatment strategies are used to lower LDL-C and non-HDL-C. All patients should be advised to undertake therapeutic lifestyle changes. Statins the drugs of choice based on an extensive record of safely reducing cardiovascular events and overall mortality. Bile acid sequestrants and niacin also reduce cardiovascular risk, although they are less effective and have more adverse effects than statins. Ezetimibe is a well tolerated drug that lowers LDL-C and non-HDL-C but has yet to be established whether ezetimibe reduces cardiovascular risk.
Fibrates are generally the first choice for triglyceride-lowering to prevent pancreatitis. However, fibrates reduce cardiovascular risk less than statins and have safety concerns when used in combination with statins. High doses of omega-3 fish oil, niacin or statins also effectively lower elevated triglycerides. The mechanisms of action, efficacy and safety for each class of drug will now be reviewed.
❑ STATINS
Statins are the foundation of cardiovascular risk reduction. Consistent evidence from more than 100,000 clinical trial participants has shown statins reduce the risk of coronary heart disease and stroke in direct proportion to the magnitude of LDLC lowering. Statins inhibit 3-hydroxy-3-methylglutarul coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis (Fig. 10).
A dose of statin should be used that will lower LDL-C by at least 30–40%. Starting doses of statins generally achieve this degree of LDL-C lowering (pitavastatin 2 mg, atorvastatin 10 mg, lovastatin or pravastatin 40 mg, rosuvastatin 10 mg, simvastatin 40 mg and fluvastatin 80 mg) (Table 10). Reducing LDL-C by more than or equal to 50% or more may be desirable, but usually requires the highest doses of atorvastatin (40–80 mg), rosuvastatin (20–40 mg), or a statin used in combination with another LDL-C lowering agent.
The majority of patients tolerate statins without difficulty. Although commonly reported, muscle complaints are usually not related to statin use. Rhabdomyolysis occurs very rarely and generally in patients with multiple factors predisposing to decreased clearance, such as advanced age, diminished renal function, and medications interfering with statin metabolism. Notably, currently marketed statins are much safer than low-dose aspirin, which has more than 200-fold higher rate of major bleeding than statins have of inducing rhabdomyolysis.
Risk of myopathy and rhabdomyolysis is related to circulating drug levels. Three statins are metabolized by hepatic cytochrome P450 enzyme (CYP) 3A4 and have the most potential for drug interactions—atorvastatin, lovastatin, and simvastatin (remember as “A, L, S”) (Table 11).44
FIGURE 10: Overview of lipid-modifying drug mechanisms.
Statins inhibit the rate-limiting step in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA reductase), which binds acetyl CoA to free cholesterol to create cholesterol esters. Reduction in intrahepatic free cholesterol (FC) increases the number of LDL-receptors (LDL-R) on the cell membrane, facilitating removal of LDL-C from plasma. Bile-acid sequestering agents (BAS) and ezetimibe (EZE) lower plasma LDL-C by lowering intracellular free cholesterol levels. BAS bind bile acids via the intestinal bile acid transporter (IBAT), interrupting the enterohepatic circulation of bile acid FC. EZE acts on the Niemann-Pick C1-Like 1 (NPC1L1) transporter in at the intestinal wall to prevent absorption of dietary and biliary cholesterol. EZE also blocks uptake of plant sterols. Dietary sterol/stanols competitively inhibit the uptake of cholesterol in the intestine. The efficacy of all three intestinally active agents is limited since there is a compensatory increase in hepatic cholesterol synthesis. Niacin acts through a unknown and known mechanisms, including partially inhibiting the release of free fatty acids (FFA) from adipose; increasing lipoprotein lipase (LPL) activity thereby enhancing removal of chylomicron (CM) triglyceride from plasma; decreasing apolipoprotein B (apo B) synthesis, which lowers very low density lipoprotein cholesterol (VLDL-C) and intermediate density lipoprotein cholesterol (IDL-C), and thus plasma triglcyerides; and increasing high density lipoprotein cholesterol (HDL-C) levels through decreased hepatic uptake, likely through the holouptake receptor (HUR) and catabolism. Increased levels of HDL-C may increase reverse cholesterol transport from peripheral cells to the liver. Fibrates lower triglyceride levels by decreasing VLDL secretion and increasing catabolism of triglyceride-rich particles via several mechanisms, including reduced apolipoprotein C (apo C) production which upregulates lipoprotein-lipase-mediated lipolysis and increased cellular FFA uptake as well as increasing FFA catabolism. Fibrates increase HDL-C, induce apolipoprotein A-I and A-II (AI & AII) synthesis via the liver X receptor/retinoid X receptor heterodimer (LXR), Omega-3 fatty acids (O-3) reduce the rate of VLDL synthesis through a number of putative mechanisms inhibiting release of FFA from adipose, inhibiting FFA synthesis, and increasing apo B degradation (Abbreviations: ABC: ATP-binding cassette; B48 or B100: Apolipoprotein B48 or B100; CETP: Cholesterol ester transfer protein; CMR: CM remnant; E: Apolipoprotein E; LRP: LDL receptor-related protein 1; PLTP: Phospholipid transport protein; SRB-1: Steroid receptor binding protein)
Avoid concomitant use of these three statins with potent inhibitors of CYP3A4, including:
- Azole antifungals (ketoconazole and itraconazole; alternative— fluconazole)
- Macrolide antibiotics (erythromycin and clarithromycin; alternative—azithromycin)
- Rifampicin and protease inhibitors (alternative—indinavir) (Table 12)
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- Lower doses of simvastatin and lovastatin are recommended for patients receiving weaker CYP3A4 inhibitors amiodarone, calcium channel blockers diltiazem and verapamil (alternatives— amlodipine and nifedipine) Interactions with some antidepressants (alternatives—paroxetine and venlafaxine) have also been reported.
Although statins are primarily metabolized by the liver, some statins have relatively greater renal excretion—lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Dose adjustment may be considered in those with markedly impaired renal excretion. All statins should be used with caution in patients with a glomerular filtration rate less than 30 since substantially impaired renal excretion is also a marker for other patient characteristics that may increase the potential for adverse muscle effects, including advanced age, frailty, and polypharmacy.
An approach to the management of muscle and other symptoms in statin-treated patients is provided in Flowchart 5. Persistent muscle pain or weakness affecting the proximal muscles is the most common manifestation of statin intolerance. The general approach is to discontinue the statin until symptoms resolve, and then rechallenge with a low dose of the same or another statin.
Abnormal liver function tests are also common among patients receiving statins but are not usually related to statin use. Persistent elevations in hepatic alanine transaminase (ALT; which is the most specific test for drug-related hepatotoxicity) 50in long-term clinical trials are uncommon and related to increasing statin dose. As long as a stable pattern of ALT elevation has been established, statins can still be used in these patients for cardiovascular prevention with regular ALT monitoring. In patients with unexplained ALT elevations greater than 3 times the upper limit of normal, the statin should be discontinued along with other potential hepatotoxic agents. The patient monitored until levels return to baseline or an etiology is established.
❑ ADD-ON TO STATIN THERAPY
Consideration may be given to adding a second agent to a statin in patients who have not achieved their LDL-C and non-HDLC goals and for whom more aggressive therapy is deemed appropriate. It should be noted, however, at this time there is insufficient clinical trial evidence that adding a second agent to statin therapy will result in additional cardiovascular event reduction. Ezetimibe, bile acid sequestrants and niacin 2 g will lower LDL-C, an additional 15% when added to statin therapy (Table 13). Niacin is more effective than other agents for lowering non-HDL-C due to greater increases in HDL-C.
❑ BILE ACID SEQUESTRANTS
Bile acid sequestrants interrupt the enterohepatic recirculation of cholesterol-rich bile acids by irreversibly binding them in the intestinal lumen (Fig. 10). Bile acid sequestrants are not systemically absorbed. Cholestyramine and colestipol modestly decrease CHD risk in long-term clinical trials, as would be expected from their modest effect on LDL-C.
As monotherapy, bile acid sequestrants at the recommended dosage will lower LDL-C by about 15% and non-HDL-C by about 10%. Bile acid sequestrants increase triglycerides on average by 15–30%, and the largest triglyceride increases occur in patients with more severe hypertriglyceridemia.
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Bile acid sequestrants are contraindicated in those with triglyceride levels more than 400 mg/dL and should be used with caution when triglycerides are 200–400 mg/dL. Colesevelam has been shown to reduce hemoglobin A1C levels by about 0.5% in diabetics with inadequate glycemic control, with greater benefit in those with hemoglobin A1C levels more than 8.0%. Notably, average triglyceride levels were less than 200 mg/dL in these studies.
Adverse intestinal effects, such as bloating, constipation and bowel obstruction, limit their use, although these effects are less common with colesevelam. Colestipol and cholestyramine decrease the absorption of anionic drugs and vitamins (vitamins A, D and K, and folic acid) and should be administered 1 hour after or 4 hours before estrogen, progestin, warfarin, digoxin, thyroxine, phenobarbitol, propranolol, thiazide diuretics, tetracycline, vancomycin, penicillin G, niacin, or ezetimibe.
❑ EZETIMIBE
Ezetimibe also acts in the intestine where it selectively inhibits uptake of cholesterol by blocking Niemann-Pick C1-Like 1 receptor, a critical mediator of cholesterol absorption, at the brush border of the small intestine (Fig. 10). By reducing cholesterol absorption from bile acids and diet, ezetimibe reduces intracellular cholesterol levels, which in turn, upregulates LDL receptors to lower plasma cholesterol levels. Statins and bile acid sequestrants act similarly through this final cholesterol-lowering pathway. Ezetimibe and its active metabolites undergo extensive enterohepatic recirculation limiting systemic exposure.
As monotherapy, ezetimibe lowers LDL-C and non-HDL-C by about 20%. When used with a statin, ezetimibe lowers LDL-C by 15–20% with a lesser effect on non-HDL-C (Table 4). A combination of tablet of ezetimibe 10 mg and simvastatin 80 mg lowers LDL-C by about 60%, similar to the highest doses of atorvastatin and rosuvastatin.
Ezetimibe has minimal adverse effects and does not appear to increase the risk of myopathy when used in conjunction with a statin. No dose adjustments are needed in patients with renal or hepatic insufficiency. Statin-ezetimibe combinations cause persistent hepatic ALT elevations greater than 3 times the upper limit of normal at a rate similar to atorvastatin 80 mg. The value of ezetimibe when added to statin therapy for cardiovascular prevention is unclear.
❑ NIACIN
Niacin can improve all lipid parameters, although effects are highly variable between patients. Therefore, niacin should only be continued in those experiencing a significant therapeutic response in the targeted lipid parameter(s) until clinical trial data are available regarding its cardiovascular risk reduction benefits added to a statin. Not all of niacin's mechanisms of action have been elucidated. Niacin lowers LDL-C and VLDLC by decreasing apolipoprotein B synthesis. Triglyceride reductions result from partial inhibition of fatty acid release from adipose tissue, leading to decreased hepatic triglyceride synthesis, as well as through increased lipoprotein lipase activity which increases the rate of chylomicron triglyceride removal from plasma (Fig. 10). Niacin-induced increases in HDL-C levels are likely related to decreased triglyceride levels, and may result from decreased hepatic uptake and catabolism of HDL-C. Niacin undergoes extensive first pass metabolism in the liver, through enzymatic pathways separate from those metabolizing statins, and is rapidly excreted in urine. Niacin has few important drug interactions although it is extensively bound to cholestyramine.52
One gram of niacin will raise HDL-C by 15% and lower triglycerides by 25%, but has little effect on LDL-C or non- HDL-C levels. At the 2 g dose, niacin will lower LDL-C by about 15%, and further increase HDL-C (+ 25%) and lower triglycerides (- 30%). Niacin 2 g will also lower lipoprotein by about 20%, although it is not known whether this will further reduce cardiovascular risk. When added to a statin, niacin retains the HDL-C raising and non-HDL-C and triglyceride lowering properties for niacin monotherapy, although some attenuation of LDL-C lowering may occur.
Immediate-release, or crystalline, niacin may have substantial cutaneous effects, such as flushing and itching, that are reduced with extended-release niacin formulations. A higher dose of aspirin (325 mg), ibuprofen 200 mg, or another nonsteroidal anti-inflammatory drug (NSAID) taken 30–60 minutes prior to niacin administration can alleviate flushing, redness, itching, rash, and dryness.
Niacin adherence may be improved titrating the dose gradually over a period of weeks to months. Flushing rates usually substantially diminish after 4 weeks of extended-release niacin use, and rarely occur after 1 year of use. Ingestion with a snack or meal slows absorption.
Doses of extended-release niacin greater than 2 g/day are contraindicated due to a very high rate of serious hepatotoxicity, including liver failure. Sustained-release niacin, which is available over the counter, should be avoided, especially in doses of more than 1.5 g daily. Serum ALT should be monitored every 6–12 weeks during the first 6–12 months of niacin treatment, and every 6 months thereafter. Niacin should be discontinued if:
- Hepatic transaminase levels are persistently more than 3 times the upper limit of normal
- Bilirubin is more than 3 mg/dL
- Prothrombin time is elevated
- Symptoms of nausea, vomiting, or malaise are present.
❑ TRIGLYCERIDE-LOWERING THERAPY
Triglycerides are not a target of therapy for cardiovascular risk reduction. Although those with triglyceride levels more than 150 mg/dL are at increased cardiovascular risk, adjustment for low HDL-C levels and insulin resistance eliminates the majority of the risk associated with elevated triglycerides. Nor are triglyceride changes from drug therapy associated with reduced cardiovascular risk. In those with severe hypertriglyceridemia (>500 mg/dL), triglycerides are the target of therapy to prevent pancreatitis.
❑ FIBRATES
Fibrates are nuclear peroxisome proliferator-activated (PPAR) receptor- α agonists that upregulate the gene for lipoprotein lipase and downregulate the gene for apolipoprotein C-III, an inhibitor of lipoprotein lipase. Lipoprotein lipase increases triglyceride hydrolysis (which decreases VLDL-C secretion) and increases catabolism of triglyceride-rich particles (Fig. 10).
Gemfibrozil undergoes glucuronidation in the liver and is 70% renally excreted. Gemfibrozil potently inhibits glucuronidation of other drugs, including all statins. Fenofibrate is also metabolized via glucuronidation and is primarily renally excreted. However, fenofibrate and fenofibric acid, its active metabolite, are much less potent inhibitors of glucuronidation than gemfibrozil, and have little 53effect on statin levels. Fibrates may substantially increase prothrombin time and international normalized ratios in patients receiving warfarin. Warfarin dose may need to be decreased by 25–35%.
Fenofibrate very modestly reduces cardiovascular risk to the degree expected from the magnitude of its modest LDL-C and non-HDL-C changes. Conversely, gemfibrozil reduces cardiovascular risk more than expected from the minimal changes observed in LDL-C and non-HDL-C. The risk reduction with gemfibrozil is independent of triglyceride changes and has been largely attributable to the use of gemfibrozil itself.
As monotherapy, fenofibrate is slightly more effective than gemfibrozil for lowering LDL-C (11% vs 1%, respectively) and non-HDL-C (18% vs 13%), although both may increase LDL-C levels in hypertriglyceridemic patients. Both drugs lower triglycerides by about 45% and raise HDL-C by about 10%.
Fibrates increase the risk of myopathy, abnormal transaminase levels, and creatinine elevations. Fibrate monotherapy increases the risk of myopathy. The risk for gemfibrozil is twofold higher than for fenofibrate. When used with a statin, gemfibrozil has a 33-fold higher risk of myopathy than fenofibrate, in part due to greater inhibition of glucuronidation. Fenofibrate appears to have little impact on statin blood levels, and so is the drug of choice for combination with low-to-moderate dose statins.
Rises in creatinine levels can occur in patients taking fenofibrate, although the clinical significance of this is unclear. The dose of fenofibrate should be reduced if creatinine rises above the normal range, and the patient carefully monitoring for adverse effects. Fenofibrate dose should be reduced in patients with glomerular filtration rates less than 60 mL/min/1.73 m2, and fenofibrate completely avoided when it is less than 15 mL/min/1.73 m2. Fenofibrate is nondialyzable and must be avoided in dialysis and renal transplant patients. A reduced dose of gemfibrozil can be used in these patients. Gemfibrozil also has significant renal excretion and concomitant use with statins with renal clearance should be avoided.
❑ OMEGA-3 FATTY ACIDS
The omega-3 fatty acids eicosopentanoic acid (EPA) and docohexanoic acid (DHA) in doses more than 3 g daily can lower triglyceride levels about as much as a fibrate. EPA and DHA come from marine sources (fish and seaweed) and are the only omega-3 fatty acids that lower triglycerides. Alpha-linolenic acid is an omega-3 fatty acid derived from land-based plant sources is minimally converted to EPA and DHA and has minimal lipid effects.
EPA and DHA, including intake from fatty fish once or twice a week, have been shown to reduce the risk of coronary death, although the mechanisms through which this occur is unclear. Triglyceride-lowering per se does not appear to reduce cardiovascular risk in studies to date. EPA and DHA are rapidly absorbed with a long half-life due to extensive incorporation into cell membranes.
A 3–4 g dose of EPA/DHA is needed to lower triglycerides by 30–45%. Very concentrated fish oil is available over-the-counter or by prescription.
The most common adverse effects of omega-3 fish oil are fishy eructation, nausea and intestinal complaints. Pharmaceutical grade fish oil is highly refined and has fewer adverse gastrointestinal effects. Doses of omega-3 fatty acids less than 6 g daily do not increase glucose levels or the risk of bleeding with aspirin or anticoagulants.54
❑ DRUGS IN DEVELOPMENT
Several drugs with novel mechanisms influencing the metabolism of LDL-C, VLDL-C, and HDL-C are in development. Several at-risk populations may benefit from LDL-C and non-HDL-C lowering agents, including those who are intolerant of statins, those with familial hypercholesterolemia or other forms of severe hyperlipidemia, and those needing additional lipid modification to reach their treatment targets.
❑ SUGGESTED READINGS
- Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39.
- National Cholesterol Education Panel. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, valuation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation. 2002;106:3143–421.
- Robinson JG, Smith B, Maheshwari N, et al. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis J Am Coll Cardiol. 2005;46:1855–62.
- Robinson JG. Pharmacologic treatment of dyslipidemia and cardiovascular disease. In: Kwiterovich P (Ed). The Johns Hopkins Textbook of Dyslipidemia. Wolters Kluwer; Phildelphia: 2010. pp.266–76.
- The Accord Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med. 2010: NEJMoa 1001282.
- The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.
- US Food and Drug Administration. FDA Drug Safety Communication: ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. March 19, 2010; http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm Accessed June 2010.
- Vandenberg B, Robinson J. Management of the patient with statin intolerance. Curr Atheroscler Rep. 2010;12:48–57.
1.5 Antithrombotic and Antiplatelet Agents
❑ INTRODUCTION
Arterial and venous thromboses are a major cause of death and disability worldwide. A majority of myocardial infarctions (MI) and cerebrovascular accidents (CVA) are caused by unregulated arterial thrombosis after rupture of an atherosclerotic plaque. Venous thromboembolism (VTE)—deep vein thrombosis (DVT) and pulmonary embolism (PE)—and embolic stroke secondary to atrial fibrillation (AF) are the result of pathologic venous clot. As prevention and treatment of these entities is fundamental to the discipline, anticoagulants are an elemental component of the cardiologist's armamentarium. Warfarin, heparin, and aspirin have been the standards of antithrombotic and antiplatelet therapeutics, but in the past 15 years low molecular weight heparins (LMWH) and the platelet ADP receptor antagonist clopidogrel have markedly altered the standards of treatment.55
❑ CLOTTING, A PRIMER
Prior to discussing individual agents, a brief update on thrombosis: the classic, waterfall cascade, as described by Davie and Ratnoff in 1964, served as a useful basis for understanding the mechanisms underlying clotting (Fig. 11) The addition of an “extrinsic” pathway, triggered by tissue factor (TF) activation of factor VII after endothelial injury, and recognition of factors V and VIII as cofactors transformed the linear cascade into a Y. This new schema placed factor Xa (fXa) in a central position as the first, integrative step of a common pathway. Conveniently, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) are well suited to interrogate for gross abnormalities in the enzymes constituting the intrinsic and extrinsic portions of the cascade.
Subsequent research has revealed additional components of the clotting system and highlighted the importance of feedback and inhibition (Fig. 12). Understanding of the central role played by thrombin has lead to the development of new direct thrombin inhibitors (DTI) that show promise in treating venous and arterial thrombi. The second development is discovery of multiple platelet signaling pathways. The recognition of additional activating pathways—unaffected by aspirin—has lead to the development of new antiplatelet agents that are essential for treatment of arterial thrombi.
❑ ANTITHROMBOTIC AGENTS
Heparins and Indirect Xa Inhibitors
Unfractionated heparin (UFH) is the prototype intravenous anticoagulant. Derived from porcine intestinal mucosa, UFH is a polysaccharide with average molecular weight of 15 kDa. A specific pentasaccharide sequence within this polymer binds to antithrombin III (AT), inducing a conformational change that allows direct and potent fXa inhibition. The AT-heparin complex also inhibits thrombin.
FIGURE 11: Classic waterfall cascade: initially conceived as a linear series of reactions in which each enzyme activated the next to produce fibrin. Original enzyme names are denoted in black with conversion to active enzyme in red using current nomenclature. Although TF and factor VII were not recognized as part of the original clotting cascade, it depicted the sequence of reactions of the intrinsic pathway quite accurately
FIGURE 12: Clotting cascade as currently understood: the intrinsic pathway (upper left) proceeds through factors XI, IX and VIII to activation of fX. Activation of fXI can occur through fXIIa, as occurs after addition of a negatively charged trigger in the aPTT, or through thrombin feedback. After endothelial injury, exposed tissue factor complexes with and activates fVII via the extrinsic pathway, which activates fX in turn. The common pathway integrates procoagulant signal and leads to conversion of fibrinogen to fibrin by thrombin. Thrombin and fXa, the two principal anticoagulant targets, are components of the common pathway. Legend: proenzymes are gray. Active enzymes are black and denoted by an a. Black arrows signify activation reactions. Molecules astride the arrows are activating proteases. Enzymes depicted in smaller type act as cofactors for coagulation proteases. Green, dotted arrows signify action by thrombin as an activating enzyme. Antithrombotic molecules are written in red and their sites of action are denoted by red dotted lines
The UFH does not enhance AT inhibition of thrombin, but rather serves as a physical bridge, approximating the two molecules. A heparin must have 18 or more saccharide units (MW ~ 5.4 kDa) to facilitate AT-thrombin interaction. Given the average size of a UFH molecule, the vast majority can inhibit thrombin and fXa (an inhibition ratio of 1:1).
Unfractionated heparin can be used in any situation in which parenteral anticoagulation is required. UFH is well suited to short-term or high-risk anticoagulation due to its short half-life (1–2 hours) and potential for reversal with protamine. There are a small number of indications in which heparin is the current standard of care (bivalirudin, discussed below, may replace UFH for indication 4):
- Patients with a high bleeding risk with indication for short-term anticoagulation.
- Patients with renal impairment; as LMWH is cleared by the kidneys, it is contraindicated in patients with CrCl <30 mL/min. UFH is not dependent on renal excretion.
- Massive PE or extensive DVT; LMWH was not studied in these populations.
- PCI; short half-life, ease of point-of-care monitoring with aPTT or activated clotting time (ACT).
- Cardiopulmonary bypass (CPB) and other extracorporeal circuits due to experience and full reversibility.
The UFH is extensively bound to plasma proteins (including platelet factor 4 (PF4) and high molecular weight vWF multimers) whose concentrations vary from patient to patient. The effect on individual patients is variable and UFH must be monitored to achieve appropriate anticoagulation. The aPTT should be tested 4–6 hours after the initiation of therapy. Once the therapeutic aPTT is reached, usually 1.5–2 times reference, UFH can be safely monitored on a daily basis so long as dosing remains constant. The UFH also requires regular monitoring of platelet count due to the risk of heparin-induced thrombocytopenia (HIT, also known as HTTS).
Low Molecular Weight Heparins
Low molecular weight heparins (LMWH) including enoxaparin, Dalteparin, and nadroparin. LMWH exerts majority of its effect through indirect inhibition of fXa with an anti-Xa/anti-IIa ratio of ~3.8. In contrast to heparin, exclusively renal excretion occurs in a dose-dependent fashion.
The LMWH has high (90%) bioavailability, which translates to predictable plasma levels after SQ administration. The half-life of most LMWH is approximately 4 hours, which allows daily or BID administration. These properties allow weight-based administration without a daily monitoring requirement, a significant convenience and cost advantage. The LMWH is also better suited for long-term therapy, as patients can self-administer SQ injections. The appropriate use of LMWH in the catheterization lab remains unsettled, due to potential increased bleeding risk, and falls outside the scope of this chapter. LMWH have the following FDA indications:
- Prophylaxis of DVT in patients undergoing abdominal surgery (40 mg SQ daily), total knee replacement or total hip replacement (30 mg SQ BID) and medically ill patients (40 mg SQ daily) with limited mobility
- Inpatient treatment of acute DVT with or without PE
- Outpatient treatment of acute DVT without PE
- Prophylaxis of recurrent ischemia in patients with unstable angina and NSTEMI in conjunction with aspirin
- Treatment of acute STEMI with thrombolysis in conjunction with aspirin; whether managed medically or subsequent PCI
- Extended treatment of VTE in patients with cancer (dalteparin).
Fondaparinux
Fondaparinux is a synthetic analogue of the ATIII binding pentasaccharide sequence found in heparins, producing equivalent fXa inhibition to LMWH. Administered in IV form only, it is 100% bioavailable.
Although theoretic advantages of fondaparinux exist, including more predictable dosing, evidence is lacking that fondaparinux is superior to LMWH. The drug is broadly approved for treatment of:
- Acute DVT
- PE
- DVT prophylaxis in a manner similar to LMWH.
Fondaparinux has been found to be non-inferior at 9 days with respect to patient outcomes with fewer bleeding episodes and improved 30 days mortality in the OASIS-5 study. Based on these findings, fondaparinux receives a class 1 indication as alternative therapy to either UFH or LMWH in the recent ACCF/ 58AHA Focused Update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST Elevation Myocardial Infarction. However, guiding catheter thrombosis and other intraprocedural thrombotic effects were increased in patients treated solely with fondaparinux who underwent subsequent PCI. This finding greatly tempered enthusiasm for the drug as a potential UFH replacement in ACS.
Overall, similar to LMWH, fondaparinux is principally cleared by the kidneys, and is contraindicated in patients with CrCl less than 30. Unlike LMWH, it is contraindicated in patients less than 50 kg, which may exclude a large number of elderly patients and women.
Idrabiotaparinux
Idrabiotaparinux is a hypermethylated fondaparinux derivative with half-life of 130 hours, designed as a once weekly drug. Like fondaparinux, it is primarily excreted via the kidney. Originally developed as idraparinux, the drug was tested as extended therapy for prevention of VTE in patients with acute DVT or PE. In this study, idraparinux 2.5 mg SQ weekly was equivalent to standard therapy (LMWH and warfarin) with less observed bleeding in patients with DVT, but inferior to standard therapy after PE. The development of idraparinux was halted due to the increased risk of bleeding, long half-life and irreversibility.
Renamed idrabiotaparinux after addition of a biotin moiety, the compound was now reversible by IV administration of avidin, a protein derived from eggs. Like protamine, avidin binds tightly to idrabiotaparinux, leading to rapid clearance.
❑ VITAMIN K ANTAGONISTS (VKA)
Warfarin
Warfarin is the oral anticoagulant against which all newer anticoagulants are measured. Despite its many drawbacks (see below), it has been successfully used to treat a wide range of thrombotic conditions.
Warfarin sodium is a dicurmarol derivative that blocks addition of γ -carboxyglutamic acid (Gla) to factors II, VII, IX, X, protein C and protein S by the vitamin K epoxide reductase (VKOR) enzyme complex. Inhibition of this reaction impairs the final, activating step in hepatic synthesis of these vitamin K-dependent clotting factors (Fig. 13).
The VKA are currently indicated for the treatment of the following conditions:
- Antiphospholipid antibody syndrome (APLAS)
- Primary prevention of stroke or systemic embolism in patients with atrial fibrillation
- Secondary prevention of recurrent CVA
- Secondary CAD prophylaxis after ACS or MI
- Heparin-induced thrombocytopenia (HIT)
- Impaired LV function
- Peripheral arterial occlusive disease
- Prosthetic cardiac valve
- Endocarditis without intracerebral abscess
- Protein C deficiency
- Protein S deficiency
- Pulmonary embolism—acute treatment and secondary prophylaxis
- Venous thromboembolism (VTE, including DVT)—acute treatment and secondary prophylaxis.
FIGURE 13: Sites of warfarin effect: vitamin K is a cofactor of γ -glutamyl carboxylase, which adds a carboxyl moiety to several proteases of the clotting cascade. Proteases requiring carboxylation are II (prothrombin), VII, IX, X and anticoagulant proteins C and S. Without addition of the carboxyl group, these enzymes are inactive. Warfarin is an inhibitor of vitamin K epoxide reductase (VKOR). If vitamin K remains oxidized through inhibition of VKOR, it cannot function as a cofactor and hepatic carboxylation of these enzymes is decreased. The names of affected enzymes are blurred in the figure
Given the extensive number of indications, a dosing discussion for each is beyond the scope of this chapter and best obtained from disease specific resources, such as AHA/ACC guidelines (e.g. AF, heart failure, valvular heart disease, etc.), ACCP evidence-based clinical practice guidelines (e.g. PE, VTE, etc.) and Micromedex.
The significant cost and burden of monitoring, numerous drug interactions and a narrow therapeutic window make warfarin therapy challenging for patients and providers. Recent studies have shown that, on average, the typical patient on long-term anticoagulation for AF is within the therapeutic range just over 50% of the time. In specialized anticoagulation clinics, this percentage increases to 63%. Conversely, elevated INR (especially >4.0) places patients at risk for bleeding complications. Patient adherence is an additional barrier to successful therapy with VKAs.
❑ DIRECT FACTOR XA INHIBITORS
The direct fXa inhibitors are a new class of (primarily) orally formulated anticoagulants that have pharmacologic profiles similar to that of LMWH. The promise of this class lies in its potential to replace warfarin for long-term indications without need for routine monitoring or “bridging” during the perioperative period. Early studies indicate that the direct fXa inhibitors may also replace LMWH in some settings such as postoperative DVT prophylaxis. It remains to be seen whether the therapeutic index of these drugs is wide enough to permit use of in a broad range of clinical settings.60
Rivaroxaban
Rivaroxaban, an oral agent, is the prototype drug in this class and was approved by the FDA in late 2011 for prevention of stroke and systemic embolism in persons with atrial fibrillation. This new class of inhibitors directly inhibits fXa without involvement of AT III. Direct inhibitors can bind to the prothrombinase complex, not accessible to AT III-mediated indirect inhibitors, with resultant reduction in thrombin generation.
Rivaroxaban prolongs PT to a greater extent than aPTT, but due to variable interaction with assay reagents these values cannot be used reliably for monitoring. The compound has high oral bioavailability (>80%), reaches maximum concentration in 2–4 hours with a 7–11 hours terminal half-life. These properties permit daily, weight-based dosing, obviating the need for monitoring in many patients.
Apixaban
Apixaban is a second direct fXa inhibitor in advanced stages of testing. Like rivaroxaban, the molecule is a selective, reversible fXa inhibitor that reaches maximum plasma concentrations quickly (~3 hours) after administration, and has a prolonged half-life (8–14 hours). About 50% of absorption occurs after oral administration. The drug is metabolized, predominantly, through nonhepatic pathways with renal excretion a major (~30%) route of elimination. Uses of potent inhibitors (azole antifungals, macrolide antibiotics and PI) are contraindicated in conjunction with apixaban.
Dose ranging studies for DVT prophylaxis after orthopedic surgery, DVT and demonstrated prevention of thrombosis efficacy and acceptable safety profile. An initial comparison of apixaban (2.5 mg PO BID) to enoxaparin (30 mg SQ BID) after TKA did not demonstrate non-inferiority due to an unexpectedly low event rate. Less bleeding was observed in the apixaban group and the drugs’ safety profiles were comparable.
❑ DIRECT THROMBIN INHIBITORS
Thrombin is a key point of propagation in thrombosis and hemostasis. Not only does active thrombin convert fibrinogen to fibrin but also creates a positive feedback loop by activating factors V, VIII and XI. It also acts as a potent activator of platelets. Given this central location in the clotting cascade, it is an attractive anticoagulant target. UFH indirectly inhibits thrombin, mediated by AT III, but this complex has limited activity against fibrin-bound thrombin. The inability to inhibit fibrin-bound thrombin, the site of clot propagation, is a potentially significant limitation. The direct thrombin inhibitors (DTI) are designed to overcome this limitation. Thrombin's activity can be inhibited at three separate locations on the molecule: (i) the active, catalytic site; (ii) exosite 1, the dock for substrates, such as fibrin, and (iii) exosite 2, the heparin binding domain. Two classes of DTI are distinguished by their mechanism of inhibition. The bivalent DTI are derived from hirudin, a naturally occurring compound that was isolated from the leech in 1905—the first anticoagulant. The bivalent DTI, as the name suggests, exert their inhibitory effect through binding to exosite 1 and the catalytic site. Univalent DTI, in contrast, are small synthetic molecules that bind only to the active site.61
Hirudin
Hirudin, isolated from Hirudo medicinalis is not used as a commercial anticoagulant. The 2 recombinant hirudins (r-hirudin or lepirudin and desulfato-hirudin or desirudin) differ at a single amino acid and are used in clinical practice. Referred to generically as hirudin, the 3 molecules are pharmacologically interchangeable.
Hirudin forms an irreversible 1:1 complex with thrombin and interacts minimally with plasma proteins. Hirudin has a short half-life in patients with normal renal function. Excretion is predominantly renal. Functional half-life is extended in patients with renal dysfunction and can reach 5 days in patients with absent kidney function. The aPTT is the test for choice of monitoring hirudin anticoagulation, but the response is linear only to 60–70 seconds. Beyond that point, the aPTT will underestimate the level of coagulation.
Hirudins have two specific indications. Based on the HAT trials, lepirudin is approved for treatment of HIT complicated by thrombosis. In these studies, the incidence of new thrombosis was significantly lowered, by 93%, in the hirudin groups as compared to historical controls. The risks for limb amputation or death were equivalent in the two groups. Current standards advocate immediate heparin withdrawal, regardless of thrombosis at the time of diagnosis; followed by immediate parenteral anticoagulation until a therapeutic INR has been reached with a VKA. Given its ability to inhibit clot-bound thrombin, lepirudin was also studied as an alterative to heparin during PCI. In these studies, hirudin was more effective in prevention of ischemic end-points but not significantly better than heparin in prevention of cardiovascular death or MI at 1 week. Higher rates of bleeding and increased transfusion requirements observed in the studies negated the potential beneficial effects.
The two primary limitations of hirudins are mutually reinforcing. The extreme dependence on normal renal function to maintain predictable anticoagulation can make avoiding over anticoagulation difficult. Given the increased rate of bleeding, treatment of elderly or critically ill patients is challenging and requires close monitoring. Besides these, There is no antidote to hirudin. When bleeding is life-threatening, only specific HD filters are effective for removal.
Bivalirudin
Bivalirudin is a synthetic, bivalent DTI and hirudin analogue. Unlike hirudin, the molecule is cleaved after binding, producing transient inhibition of thrombin. Bivalirudin has a lower affinity for thrombin than hirudin by 1000-fold and does not spur antibody formation. The drug is degraded by proteolytic and hepatic mechanisms. Dose adjustment is required in patients with renal impairment.
Due to short half-life and IV formulation, bivalirudin is administered as a continuous infusion after an initial bolus. The principal indication is as an alternative anticoagulant during PCI. Bivalirudin can also be used for treatment of HIT/HTTS, but its mode of administration makes use impractical in noncritical care settings. Current FDA indications are:
- Use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)
- Use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) is indicated
- Bivalirudin is indicated for patients with or at risk of HIT/HITTS undergoing PCI.
The two main limitations of bivalirudin are its exclusively parenteral formulation and its route of excretion, requiring dose adjustment patients with renal dysfunction. Assuming normal renal function, the half-life of bivalirudin is approximately 25 minutes. Coagulation parameters return to normal 1 hour after cessation of IV infusion. As with all anticoagulants, it confers an increased risk of bleeding, but the lower rates of bleeding in the aforementioned trials make it an appropriate alternative during PCI, PTCA or CABG. The aPTT can be used for monitoring at lower levels of anticoagulation; up to 3 times the upper limit of normal. Above this limit, the test is no longer sensitive.
Argatroban
Argatroban is a synthetic, small molecule derived from L-arginine. This univalent DTI, as a prototype of the class, reversibly inhibits only the active site of thrombin. Argatroban otherwise behaves similarly to bivalirudin, inhibiting both free and clot-bound thrombin. The molecule is metabolized in the liver and excreted, principally, in the feces without significant renal involvement. Argatroban is administered intravenously. The plasma half-life is 45 minutes and steady state anticoagulation is reached in 1–3 hours.
Argatroban has two FDA indications and is used principally in patients with HIT and significant renal dysfunction:
- Prophylaxis or treatment of thrombosis in patients with HIT
- Use during PCI in patients with documented or at risk for HIT.
Efficacy data from studies has shown that prompt treatment with intravenous argatroban (to an INR of 1.5–3 for 5–7 days) which resulted in a significant decrease in new thrombosis (28% vs 38.8%) when compared to historical HIT controls treated with placebo. The principal advantage of argatroban is ease of use in patients with impaired renal function. In treatment of HIT and during PCI, no dose-adjustment of argatroban for renal dysfunction is required. In patients with HIT, the level of anticoagulation can be safely monitored using the aPTT so long as the desired therapeutic range in less than 3 times the upper limit of normal.
Allergic reactions after argatroban administration have manifested in a variety of clinical settings. Greater than 95% of these reactions occurred in patients who were concomitantly treated with thrombolytic therapy (e.g. streptokinase) or iodine-based contrast media. Coadministration with other antithrombotic or antiplatelet agents is associated with an increased risk of bleeding.
Ximelagatran
Ximelagatran was the first oral, univalent direct thrombin inhibitor to reach advanced stages of preclinical testing. Phase III trials of ximelagatran have demonstrated efficacy in several clinical settings: postoperative DVT prophylaxis, acute DVT treatment, secondary prevention of ACS, and stroke prevention in patients with AF. A British meta-analysis comparing ximelagatran to standard dose enoxaparin showed improved VTE prophylaxis, but increased serious bleeding.
Dabigatran
Dabigatran is a univalent, oral DTI that potently inhibits thrombin, similar to ximelagatran. It is approved in the EU and Canada for perioperative DVT prophylaxis in orthopedic patients. The structure of dabigatran etexilate, the orally formulated prodrug, is distinct from ximelagatran. Metabolism proceeds through plasma esterases, rather than hepatic enzymes, and it has been found to be non- 63hepatotoxic. It is theorized that rapid plasma metabolism quickly lowers inactive precursor concentrations, preventing a ximelagatran-like toxicity. The drug reaches peak plasma concentrations in 1.5 hours and exhibits a 14–17 hours half-life. Twice-daily dosing is standard.
The FDA has unanimously recommended approval the 150 mg PO BID dose of dabigatran for stroke prevention in AF. Additional recommendations include:
- A 75 mg tablet for daily use in renal impairment
- Use of 110 mg PO BID dose for patients with elevated bleeding risk
- Phase IV testing of higher dose dabigatran in the above clinical setting
A dose of 150 mg orally BID has demonstrated equivalence to standard therapy (SQ enoxaparin followed by dose adjusted warfarin) in 6-month treatment of acute VTE, both DVT and PE in the RE-COVER study. Other studies may determine whether dabigatran replaces warfarin as the drug of choice for treatment and long-term prevention of VTE. Dabigatran should immediately fill a need for patients with inadequate access to an anticoagulation clinic or for whom increased bleeding risk makes warfarin therapy unacceptable.
❑ ANTIPLATELET AGENTS
Platelets instigate and catalyze arterial thrombosis in a stepwise process (Fig. 14). Each step presents a potential therapeutic target for inhibition of thrombosis. At injury outset, platelets adhere to sub-endothelial matrix components, minimizing the breach in the endothelial wall. Although few therapeutics that interrupt adherence have been studied, development potential will be discussed briefly.
FIGURE 14: Antiplatelet agents: Depicted at right are the major sites of action of the five extant classes of antiplatelet drugs. Aspirin is the major inhibitor of the TXA2 pathway. Clopidogrel and ticagrelor inhibit P2Y12 activation by ADP. GP IIb/IIIa inhibitors inhibit fibrinogen binding and platelet aggregation
Also exposed by endothelial injury, TF binds factor VII, initiates the clotting cascade and generates thrombin, which is a potent activator of platelets. ADP and TxA2 are also crucial signals that lead to platelet activation and recruitment. The most established antiplatelet therapies, aspirin (an inhibitor of TXA2 synthesis) and clopidogrel (an ADP/P2Y12 antagonist), aim to disrupt this second step. Once activated, intracellular signaling produces a conformational change in the GP IIb/IIIa (aIIbb3) receptor that favors fibrinogen binding (as well as vWF and fibronectin). Aggregation is the result of avid platelet binding, via the abundant aIIbb3, to many fibrinogen molecules. The two aIIbb3 binding regions of fibrinogen produce extensive platelet cross-linking. This final step is inhibited by the parenteral glycoprotein IIb/IIIa inhibitors (GPI), which will be discussed only briefly in this section, due to their limited use outside the catheterization lab.
Inhibitors of Platelet Adhesion
At present, there are no clinically available inhibitors of platelet adhesion. In vitro and animal models have demonstrated that inhibition of multiple receptors can reduce platelet adhesion to the subendothelial matrix. Animal models have demonstrated protection from arterial thrombosis when adhesion is inhibited. A monoclonal antibody directed against the murine GPVI receptor led to a long-term prevention from thrombosis. Together, these findings make inhibitors of adhesion an attractive target for drug development.
Aegyptin, a mosquito derived molecule has been shown to prevents in vivo aggregation and thrombosis after laser-induced carotid injury in rats without excess bleeding. Saratin, a leech derived compound, prevents platelet and vWF binding to collagen under high-shear conditions.
Inhibitors of Platelet Activation
TXA2 Pathway Inhibitors
Aspirin or acetylsalicylic acid (ASA) is the prototype TXA2 pathway inhibitor. NSAIDs, ibuprofen and naproxen, which reversibly inhibit cyclooxygenase (COX), and selective COX-2 inhibitors, such as celecoxib, are members of the class, as are ridogrel and terbogrel, which combine a TXA2 synthase inhibitor and TXA2 /prostaglandin endoperoxide receptor antagonist. While these combination drugs have theoretic advantages over aspirin, they have not proven clinically more efficacious and have produced untoward side effects.
Current indications for ASA use include:
- A dose of 325 mg daily for 1 month followed by 81 mg daily for life—ACS, including STEMI, NSTEMI and UA
- A dose of 325 mg daily for 1 month followed by 81 mg daily for life—following PCI
- A dose of 81 mg daily for life—for secondary prevention of MI in patients with CAD, PAOD or documented pulmonary artery disease
- A dose of 81 mg daily for life—after CABG, carotid endarterectomy or peripheral vascular bypass
- A dose of 1300 mg daily—for symptomatic intracranial arterial stenosis
- A dose of 81–325 mg daily—prevention of embolic stroke in patients with AF and CHADS2 score of 1 or contraindications to warfarin use
- A dose of 50–325 mg daily, preferably in combination with dipyridamole 200 mg twice daily—secondary prevention of CVA after stoke or TIA
- A dose of 325 mg once—administered 24–48 hours after acute stroke (of note, ASA is not recommended within 24 hours of thrombolytic therapy)
- A dose of 81–162 mg daily—for patients with heart failure and reduced ejection fraction
- A dose of 100 mg daily—for patients with polycythema vera and no contraindication to ASA use.
Of note, ASA is not formally indicated for primary prevention. In 2009, the US Preventative Services Task Force recommended encouragement of daily, low-dose ASA use for primary prevention of cardiovascular disease (CVD) in men aged between 45 and 79 years and women between 55 and 79 years without mention of risk factors or diabetes (DM). Recently published meta-analyses and RCT have questioned the benefit of ASA for primary prevention due to a poor risk–benefit ratio. A 2010 position statement of the American Diabetes Association (ADA) and American Heart Association was released that included the provision that recommendation of low-dose (75–162 mg) ASA in patients with DM and an elevated 10-year risk for CVD is “reasonable”. It continued that ASA should not be recommended for primary prevention in men with age less than 50 years and women less than 60 years with DM without additional CVD risk factors.
The main adverse effect of ASA is bleeding, most commonly GI, although rates are low. The yearly risk of major GI bleed is 0.05–0.1% among patients treated with low-dose ASA, twice the baseline rate. Factors that increase the risk of bleeding are:
- Increasing age
- Previous GI bleeding (GIB) or peptic ulcer disease
- Concomitant use of warfarin, NSAIDs, or steroids.
The most recent AHA/American College of Gastroenterology guidelines advocate GI prophylaxis for any patient prescribed long-term antiplatelet therapy. For patients on dual antiplatelet therapy, such as ASA and clopidogrel, a PPI is the recommended agent to prevent GI bleeding. For patients on single antiplatelet therapy, PPI is recommended when gastroesophageal reflux disease or the above risk factors are present.
Increased postoperative bleeding, but not death, has also been reported after CABG in patients with preoperative ASA use. This effect was observed only in conjunction with doses greater than or equal to 325 mg daily. This finding would indicate that continuation of low-dose ASA, rather than cessation 5 days prior, would be appropriate therapy for patients undergoing CABG. Cessation of antiplatelet therapy after MI or stent placement, especially within the recommended treatment windows, is associated with elevated risk of thrombosis.
Inhibitors of ADP/P2Y12 Signaling
Clopidogrel: (Plavix) is the prototype P2Y12 inhibitor, a second-generation thienopyridine. The first generation drug of this class, ticlopidine, is discussed subsequently. Thienopyridines selectively and irreversibly inhibit the P2Y12 receptor, reducing ADP-dependent platelet aggregation. After ingestion, 15% of clopidogrel is converted to an active metabolite by the hepatic CYP system. Within 2 hours of a 300 mg oral dose, the active metabolite produces 40% inhibition of ADP-induced platelet aggregation. Due to irreversible P2Y12 inhibition, platelet inhibition is maintained for 48 hours, despite the 8-hour half-life of the active metabolite.66
After loading, daily administration of 75 mg increases platelet inhibition to approximately 60%, the maximum achievable. A larger loading dose; 600 mg, achieves maximum platelet inhibition in 2 hours. Clinically, loading with 600 mg prior to PCI improves 30-day clinical outcome without increasing rates of bleeding.
Clopidogrel was approved on the basis of a single large trial, in which it (75 mg daily) was compared directly with ASA 325 mg daily for secondary prevention of CVD in patients with symptomatic peripheral arterial disease (PAD), recent MI or recent ischemic stroke (both <35 days). Current indications for clopidogrel include:
- ACS
- ▪ For patients with NSTEMI or unstable angina, a 300 mg loading dose followed by 75 mg daily in combination with daily ASA
- ▪ For patients with STEMI; 75 mg daily in combination with ASA, with or without thrombolytics. Loading dose is optional in this setting, but 600 mg appears appropriate for patients proceeding to PCI
- Secondary prevention of CVD with documented MI, stroke, or PAD.
Dual antiplatelet therapy may improve secondary prevention in the highest risk patients, but increased bleeding has limited wide use. Current indications do not specify duration of dual antiplatelet therapy, but the recommended minimum length of therapy for patients implanted with bare metal stents is 1 month. Optimal duration of dual antiplatelet therapy after DES remains uncertain due to reports of stent thrombosis beyond 1 year.
Incidence of bleeding increases when clopidogrel is added to ASA as part of dual antiplatelet therapy. As discussed above, PPI is currently indicated for all patients receiving dual antiplatelet therapy. Concern has arisen that concomitant use of PPI and clopidogrel attenuates the effect of the latter.
A black box warning was recently added to clopidogrel, warning of adverse events among patients with genetic polymorphisms of 2C19 that impair metabolism. An ACCF/AHA response did not advise routine CYP testing or alteration of clinical practice, citing a paucity of prospective outcome data or predictive value of routine genetic testing.
Prasugrel
Prasugrel is a third generation thienopyridine. Like clopidogrel, an active metabolite irreversibly inhibits the P2Y12 receptor. The liver converts prasugrel more efficiently to its active metabolite compared to clopidogrel. Prasugrel produces complete inhibition of platelet aggregation by 1 hour. Despite structural similarities, prasugrel is unaffected by common polymorphisms of 2C19 and 2C9, another CYP450 enzyme implicated in reduced clopidogrel metabolism. These pharmacologic distinctions have correlated with increased in vivo platelet inhibition when compared to clopidogrel.
Prasugrel was approved for clinical use in 2009. Prasugrel is currently indicated for:
- Patients with unstable angina or NSTEMI
- Patients with STEMI when managed with immediate or delayed PCI.
A class III recommendation (indicating harm) regarding prasugrel has been included in the most recent STEMI and UA/SNTEMI guidelines.160,281 It should not be used in patients with “history of stroke and transient ischemic attack for whom primary PCI is planned, prasugrel is not recommended as part of a dual-antiplatelet therapy regimen.” Prasugrel received an extensive black box warning based on the increased risks for bleeding. Prasugrel is contraindicated in patients with age more than 75 years, except for those at highest risk, due to increased risk of fatal and ICH. The drug is contraindicated if urgent CABG is ‘likely’ and should be discontinued 7 days prior to any surgery.67
Phosphodiesterase (PDE) Inhibitors Dipyridamole
The prototype drug in the class, acts by increasing intracellular levels of cyclic adenosine monophosphate (cAMP). Increased cAMP levels, in turn, reduce platelet activation by inhibiting calcium mobilization. Several in vitro mechanisms of action have been demonstrated; inhibition of platelet PDE, reduction of adenosine uptake by platelets and stimulation of prostacyclin (PGI2) release by endothelial cells.
Indications and efficacy: Dipyridamole was introduced for treatment of angina. The antiplatelet properties of the drug were discovered later, leading to its repurposing as an antithrombotic agent. It has proven ineffective as a lone anticoagulant. The current indications for dipyridamole are:
- 100 mg four times daily in conjunction with warfarin to reduce thrombotic complications after implantation of a mechanical heart valve
- Extended-release dipyridamole (ERDP) 200 mg in conjunction with ASA 25 mg used twice daily for secondary prevention of stroke after TIA or completed ischemic stroke due to thrombosis.
Headache is the principal adverse effect of dipyridamole treatment, affecting one-third of treated patients and a leading cause of drug discontinuation. Increased rates of diarrhea and other GI complaints have also been reported. The combination is contraindicated in patients with severe hepatic impairment or severe renal impairment (GFR <10 mL/min).
Cilostazol: Cilostazol is an inhibitor of platelet PDE3A, which like dipyridamole, also acts as a vasodilator. Thrombin activates PDE3A (via PAR-1, below), reducing the intracellular cAMP concentration and promoting platelet activation. Given the antagonism of thrombin signaling in platelets, it is not surprising that cilostazol exerts antiplatelet effects. The principal route of drug metabolism is hepatic (CYP3A4 and 3A5) and fecal excretion predominates.
Cilostazol was granted FDA only for approval for the treatment of symptomatic claudication in a dose of 50–100 mg twice daily. Cilostazol treatment has been shown to significant increases in pain-free walking distance for patients with disabling disease (but without limb ischemia or pain at rest). More recently, cilostazol has been tested as an adjunctive antiplatelet therapy after PCI. The addition of cilostazol to dual antiplatelet therapy after bare metal stent placement was associated with decreased angiographic stenosis at 6 months. No reduction in MI or mortality was reported in the association with the reduction in stenosis. The effect was most pronounced in diabetic subjects, long lesions and small-diameter vessels, situations in which DES would be preferentially used.
The principal adverse effects of cilostazol are headache and diarrhea, as with dipyridamole. Palpitations are the unique side effect associated with cilostazol. Caution should be exercised when cilostazol is used in concert with inhibitors of CYP3A4/5 such as macrolide antibiotics, selective serotonin reuptake inhibitors, azole antifungals and warfarin. Additionally, grapefruit juice was associated with purpura in a patient using cilostazol.
Thrombin Receptor Antagonists
Thrombin signaling via PARs appears to be the most potent of the three parallel platelet activation pathways.
Vorapaxar: Vorapaxar is an oral inhibitor of PAR1 and prototype thrombin receptor antagonists (TRA). Vorapaxar was derived from himbacine, a compound isolated 68from the bark of the Australian magnolia. Vorapaxar dose-dependently inhibited platelet aggregation in vitro and does not affect traditional measures of coagulation. The drug is rapidly absorbed but slowly eliminated with a half-life of 165–311 hours. Return of platelet function occurs, on average, 1 month after drug cessation. The drug is excreted in the feces and dose adjustment for renal function in not required.
Inhibitors of Platelet Aggregation
Three glycoprotein IIb/IIIa inhibitors (GPI) have received FDA approval for use in ACS or adjunctive therapy during PCI. In aggregate, these agents significantly reduce death and MI through 6 months. Oral GPI have shown no clinical benefit and are associated with increased mortality. The clinical indications for GPI use have become more limited with time. A complete discussion of GPI indications and use is located in sections discussing catheterization and PCI.
The first approved agent, abciximab, is a chimeric protein composed of Fab (fragment, antigen binding) regions from the murine 7E3 antibody and the Fc of human immunoglobulin. Abciximab in conjunction with coronary stenting has shown to lead to a marked improvement in clinical outcome at both 30 days and 6 months. Abciximab has demonstrated benefit over placebo in patients with elevated troponin at the time of PCI. Abciximab is not cleared by the kidneys and is safe in patients with CKD or ESRD.
Eptifibatide: is small molecule GPI modeled after a component of pigmy rattlesnake (Sistrurus miliarius barbouri) venom. A peptide-based compound, eptifibatide binds tightly to aIIbb3, producing dose-dependent reversible inhibition. Significantly lower rates of MI and death occurred in patients with ACS treated with eptifibatide, in addition to heparin and ASA, with or without subsequent PCI. The ESPRIT trial demonstrated reduced rates of MI and death at 1 year when used in conjunction with standard therapy during PCI. Subsequently no benefit was reported with scheduled eptifibatide prior to PCI as compared to provisional use after procedural thrombotic complication.
Tirofiban: Tirofiban is a second small molecule, nonpeptide GPI. Although never compared directly with eptifibatide, it is used interchangeably due to similar mechanisms of action and clearance. When compared directly to abciximab, tirofiban use was associated with increased rates of MI.
❑ SUGGESTED READINGS
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- Briefing Information for the September 20, 2010 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm226008.htm.
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- The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354: 1464–76.
- The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med. 1998;3381488–97.
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