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Medical Management of Vascular Disease―Including Pharmacology of Drugs Used in Vascular Disease Management
Introduction
Arterial disease is the leading cause of death and significant morbidity in the United States and throughout the world. The American Heart Association estimates that 85.6 million (26.4%) Americans have cardiovascular disease, leading to 787,000 deaths annually. Patients with peripheral arterial disease (PAD) make up a significant proportion of this group, including 795,000 Americans who will have strokes each year. Stroke itself is the third leading cause of death in the Unites States, with an estimated 129,000 patients dying each year. Those who do survive often have significant neurologic deficits, which can become major social and economic burdens to the patients and their families.
PAD is a significant public health issue due to the need for extensive long-term care for patients with these serious disabilities, but also given that much of atherosclerosis and therefore PAD is preventable or diminishable by avoiding tobacco, fatty foods, and taking medications regularly to control hypertension, diabetes, and hyperlipidemia. It is estimated that for 2015, the total direct and indirect cost of cardiovascular diseases and stroke in the United States was $320.1 billion.
In this chapter we will discuss the risk factors for development of atherosclerosis, discuss the clinical relevance of the disease, discuss preventative modalities and evolving medical treatments, and review the pharmacologic agents used in vascular disease management.
Atherosclerosis—Basic Principles and Medical Management
Risk Factors for Atherosclerotic Disease and Modification Strategies
Cardiovascular disease is increasingly recognized as the largest growing burden of disease for health care systems. Although current treatment regimens and surgical outcomes for atherosclerotic disease have improved morbidity and mortality, the current emphasis has been focused on effective clinical guidelines for prevention and modification at an earlier stage in the disease process. Box 13.1 lists the most common risk factors for atherosclerotic cardiovascular disease.
Box 13.1
Risk Factors for Atherosclerotic Cardiovascular Disease
Smoking
Smoking is the greatest contributor to atherosclerotic cardiovascular disease and the number one cause of preventable deaths in the United States per annum. Smoke-related deaths continue to rise, particularly in the developing world.
A dose-related phenomenon has been described for cigarette-smoking that correlates with increased rates of coronary events, ischemic strokes, and peripheral vascular disorders. Despite this dose effect, complete smoking cessation has been demonstrated to be the only significantly effective approach to reducing health risks associated with smoking. As much as a third of cardiovascular mortality can be prevented by abstinence from smoking, an effect that has not yet been realized by pharmaceutical risk-factor management.
Effective holistic treatment plans exist for patients who are motivated to cease smoking, such as nicotine replacement by transdermal patch or chewable gum, behavioral modification, and antidepressant or medical therapy.
Diabetes Mellitus
Diabetes mellitus (DM) rivals smoking in contribution to cardiovascular mortality, as evidenced by the fact that coronary artery disease (CAD) is the principal cause of death in diabetic patients. The rate of coronary and PAD approximately doubles in patients who carry a diagnosis of diabetes. The length of time and severity of diabetic control are strong predictors of atherosclerotic events and have been correlated with the degree of PAD experienced by patients. The microvascular complications of diabetes are beyond the scope of this chapter, but diabetic nephropathy, heralded by microalbuminuria, exacerbates large vessel changes imposed by insulin resistance and hyperglycemia. Atherosclerosis can be shown experimentally to be induced by insulin resistance preceding the development of a clinical diagnosis of diabetes, and has been diagnosed in adolescents and teenagers as part of the metabolic syndrome.
Significant improvements in the glycemic profile and reduction in diabetic complications with prolongation of life expectancy can be achieved through behavioral modification of diabetes. Level 1 data from large randomized national trials of monitored lifestyle modification demonstrate up to 30% reduction in frank diabetes with associated reduction in cardiovascular events. The addition of effective glycemic agents such as metformin, sulfonylureas, and thiazolidinediones further contributes to cardiovascular risk reduction. Current glucose targets for diabetic patients are listed in Box 13.2 . A causal relationship has been described for long-term blood glucose control, as assessed by the hemoglobin AIc (HbA1c) in the national United Kingdom Prospective Diabetes Study (UKPDS), with an increase in the risk of adverse cardiovascular events for each percentage point above an HbA1c level of 6.2%. The UKPDS recommendations for metabolic control of diabetic patients also focus on other parameters that are known to interact deleteriously with diabetes to increase cardiovascular risk such as hypertension and hyperlipidemia. Physicians now recognize the need for aggressive management of patients with the constellation of diabetes, hypertriglyceridemia, hypertension, and obesity, some of which will fit the definition of the metabolic syndrome.
Box 13.2
Current Target Guidelines for Diabetic Patients
| Fasting blood glucose <110 mg/dL |
| Hemoglobin A1c <7% |
| Blood pressure <130/80 (combination HCTZ/ACEI as first-line therapy) |
| LDL <100 mg/dL (<70 mg/dL considered if established coronary artery disease) |
| Triglyceride level <150 mg/dL |
ACEI, Angiotensin-converting enzyme inhibitor; HCTZ, hydrochlorothiazide; LDL, low-density lipoprotein.
Hypertension
The prevalence of hypertension in the United States is estimated at one in three individuals. Part of the difficulty in managing hypertension is the racial disparity in prevalence, response to antihypertensive medications, and associated exacerbating factors such as renal disease and diabetes. High-risk groups include African Americans, those older than 60 years of age, and women. A dose phenomenon has been described for hypertension. In general an elevation in blood pressure of 20 mm Hg systolic from a theorized normal of 120 mm Hg systolic confers a cardiovascular risk double that of the normotensive population. A working definition of hypertension is a systolic blood pressure (SBP) greater than 140 mm Hg or a diastolic pressure greater than 90 mm Hg. Prehypertension can be defined further as blood pressure ranging between 120 and 139 mm Hg systolic and 80 to 89 mm Hg diastolic. Almost two-thirds of patients with hypertension have at least one other risk factor for cardiovascular disease, and thus treatment of hypertension should be ideally managed by using therapies that are multivariate in effect—for example, dietary modification or pharmacological agents with benefits for both triglyceride and blood pressure profile.
The 2014 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-8) panel published guidelines that summarize management goals for the treatment of hypertension. Those recommendations include initiating antihypertensive therapy in patients younger than 60 years of age with SBP greater than 140 mm Hg or diastolic blood pressure (DBP) greater than 90 mm Hg. In patients older than 60, antihypertensive treatment should be initiated for an SBP greater than 150 mm Hg or a DBP greater than 90 mm Hg. All adult patients with DM or chronic kidney disease should have antihypertensive therapy initiated for SBP greater than 140 mm Hg or DBP greater than 90 mm Hg. For the general population, initial therapy should include a thiazide diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). Initial therapy for black patients without chronic kidney disease (CKD) should be limited to thiazide diuretics or CCBs, while all patients with CKD should use an ACEI or ARB as an initial therapy for hypertension. With regard to lifestyle modifications for the management of hypertension, the JNC-8 does not make specific recommendations, but supports the recommendations of the 2013 Lifestyle Work Group. These recommendations include following the DASH eating plan (Dietary Approaches to Stop Hypertension), consisting of a diet rich in fruits, vegetables, and low-fat dairy products, and limiting intake of sodium, saturated fat, and trans-fat. In addition, they recommend and regular aerobic activity for at least 40 minutes most days of the week.
Dyslipidemia
Low-density lipoprotein (LDL) is firmly established in cardiovascular risk profiling as the major contributor to atherosclerotic disease and is found in abundance in atherosclerotic plaque. Higher serum levels of LDL correlate with a higher risk of cardiovascular disease; data borne out of clinical studies indicate LDL as the main risk factor for coronary disease. The Post-Coronary Artery Bypass Graft (Post-CABG) trial examined this relationship further and attempted to define a threshold target level for LDL. From this work, guidelines were drawn up supporting intensive LDL treatment to a level lower than 100 mg/dL to influence a favorable change in atherosclerotic plaque morphology (see Box 13.2 ).
Although LDL has been identified as a target for cardiovascular risk reduction, other lipid and lipoprotein abnormalities have been recognized in contributing to the overall risk of atherosclerotic disease. Elevated levels of very-low-density lipoprotein (VLDL), apolipoprotein B, and decreased high-density lipoprotein (HDL) are adverse markers for cardiovascular risk. Clinical evidence for the involvement of these lipoproteins is found in the acceleration of atherosclerotic buildup, seen in patients suffering from inherited forms of dyslipidemia such as familial hypercholesterolemia.
First-line therapies for reducing cholesterol, LDL, VLDL, and increasing HDL involve behavioral modification in the form of dietary changes. Simply reducing body weight toward goal body mass index will produce significant reductions in LDL levels and reduce the overall cardiovascular risk profile.
The main pharmacological modality employed to impair cholesterol metabolism is the hydroxymethylglutarate coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors or “statin” medications). The mechanism of statin action occurs at the hepatocellular level to inhibit cholesterol synthesis in the liver. Statins are powerfully effective in reducing total body LDL levels (from 30% to 60%, depending on dosage). Not surprisingly, these medications have become first-line drug therapy for patients with elevated lipid profiles in the absence of drug contraindications. Myopathy, heralded by a rise in creatine kinase, and transient elevation of hepatic aminotransferases are the most commonly quoted side effects of statin use. These derangements usually resolve with discontinuation of the medication.
Statins, along with four other medications used in the treatment of dyslipidemias (ezetimibe, niacin, fibric acid derivatives, and bile acid sequestrants), will be discussed as follows.
Metabolic Syndrome
Over the past half-century a constellation of metabolic derangements have been seen more frequently occurring in association. Hypertension, DM, obesity, and dyslipidemia are the four entities most commonly described as part of the metabolic syndrome or colloquially known as syndrome X. According to the definition drawn up by the 2001 Adult Treatment Panel III of the National Cholesterol Education Program (NCEP), metabolic syndrome is diagnosed when three of the following criteria are present :
- 1.
Central obesity—waist circumference >102 cm (M), >88 cm (F)
- 2.
Fasting plasma glucose >6.1 mmol/L
- 3.
Hypertension ≥135/85 mm Hg, or the presence of antihypertensive medications
- 4.
Dyslipidemia, including triglycerides ≥1.7 mmol/L, HDL cholesterol <1.0 mmol/L (M), <1.3 mmol/L (F)
For many of the reasons highlighted earlier in the chapter, the metabolic syndrome is strongly associated with the development of cardiovascular disease, portending an approximately 2.5 times risk of fatal cardiovascular events in the population. The single most effective treatment for the metabolic syndrome is the loss of body weight either by nonsurgical or surgical means, which in almost all cases of dramatic weight loss leads to amelioration of all individual components.
Emerging Novel Risk Factors
Although the previously provided well-established risk factors have been strongly linked to the development of cardiovascular disease, there remains a significant proportion of the atherosclerotic population that does not possess these described risk factors. Searches for other contributing factors have focused on molecular biomarkers as diverse as homocysteine levels, high-sensitivity C-reactive protein (hs-CRP), fibrin-degradation products (FDP), and microalbuminuria.
Elevated plasma homocysteine levels have been cited as a defined risk factor for the development of atherosclerotic coronary arterial disease in epidemiological as well as clinical research studies. On a molecular basis, high levels of homocysteine have been demonstrated to occur with disruption of normal methionine metabolism. Homocysteine and related metabolites can be detected in abnormally high levels in the blood and have been linked to an increased risk of stroke, due to carotid plaque buildup, as well as cardiovascular disease. Therapeutic options for individuals diagnosed with homocysteinemia have centered on the replacement of vitamin B12 and folic acid as a primary treatment, with additional restriction of dietary intake of methionine in vitamin B12-insensitive patients. However, studies have not, as of yet, shown that lowering homocysteine levels decreases the risk of cardiovascular disease in these patients.
The elevation of inflammatory markers such as hs-CRP and FDP is considered to be associated with cardiovascular disease. Although originally thought to play a role as potential serum biomarkers of cardiovascular disease, hs-CRP and FDP have only been weakly associated with risk stratification and burden of atherosclerotic disease.
hs-CRP has recently been the subject of much attention with the results of the JUPITER trial—a large multinational, double-blind placebo-controlled trial of more than 17,000 people. The trial was designed to observe the effect that treatment with a statin (rosuvastatin) had on individuals with normal lipid profiles but elevated hs-CRP levels. The study arose from the observation that statins have an antiinflammatory property and decrease hs-CRP levels in an effect that is independent from their cholesterol-lowering ability. The JUPITER trial demonstrated a reduction in both LDL and hs-CRP levels to around half of pretreatment and was terminated prematurely on the basis of this beneficial result. However, the benefit of a normal hs-CRP has not yet been firmly established as a treatment goal in cardiovascular risk profiling and is additionally confounded by the possible benefit of statin therapy in the face of normal lipid profile in certain populations. These findings have, however, motivated further investigation into the association between inflammation and cardiovascular disease in the form of two large placebo-controlled trials: the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) and the Cardiovascular Inflammation Reduction Trial (CIRT).
Microalbuminuria is a sensitive predictor of mortality and highly associated with cardiovascular adverse events in specific. Diabetic and hypertensive nephropathy can be diagnosed reliably by evidence of proteinuria, which is also associated with an increase in cardiovascular risk profile. Microalbuminuria is similarly associated with an elevated risk of coronary disease, independent of proteinuria, and thus may have clinical utility in patients who do not carry a diagnosis of hypertension or diabetes as a screening tool for atherosclerotic disease. Treatment strategies based on the detection of microalbuminuria are therefore likely to take the form of existing risk-reduction strategies for well-established cardiovascular risk factors.
Surveillance and Secondary Prevention
Given the focus on prevention of atherosclerotic disease, increased surveillance for the development of signs of atherosclerotic disease in those with established risk factors should be included in the routine health care maintenance and follow-up of patients. Regular carotid duplex evaluation for older patients with one or more risk factors for atherosclerosis in addition to at least annual physical examinations is a relatively inexpensive and highly effective screening tool for carotid disease. Similarly, screening aortic ultrasonography, physical examination, and ankle-brachial pressure indices should be considered for at-risk patients in the primary care setting.
For those patients who progress to severe or acute cardiovascular disease, secondary prevention guidelines are well documented and rigorously studied. Many cardiovascular centers have established protocols for treating patients with established disease. One such example is the University of California, Los Angeles CHAMP (Cardiac Hospitalization Atherosclerosis Management Program), which focuses on employing secondary prevention measures while patients are in the hospital in order to improve clinical outcomes. The CHAMP guidelines are summarized as follows:
- 1.
Aspirin 81 to 162 mg daily should be initiated. In the presence of contraindications to aspirin, other platelet agents should be considered—for example, clopidogrel. Combination therapy can be recommended in the setting of acute coronary syndromes (ACS) or post-revascularization therapy.
- 2.
Statin therapy should be initiated in all patients in the absence of contraindications and in all diabetic patients regardless of their lipid profile. Target levels of LDL should be less than 70 mg/dL, HDL greater than 40 mg/dL, and triglycerides less than 150 mg/dL.
- 3.
ACEI or ARB should be commenced in the absence of contraindication, irrespective of the blood pressure or cardiac ejection fraction.
- 4.
Beta blockade should be prescribed for all patients in the absence of contraindication.
- 5.
Fish oil or omega-3 fatty acids should be commenced with dietary instruction for all patients.
- 6.
Aerobic exercise programs that involve 30 to 60 minutes of moderately intense exercise at least five times a week should be prescribed.
- 7.
Smoking cessation should be pursued including access to formal smoking cessation programs.
- 8.
Before hospital discharge and at 6 weeks follow-up, cardiovascular lipid profile and liver enzymes should be checked and routinely thereafter at future follow-up appointments.
Pharmacology of Drugs Used in the Management of Vascular Disease ( Table 13.1 )
Anticoagulants
Heparin
Structure and mechanism of action.
Heparin is an anticoagulant composed of a heterogeneous group of straight-chain glycosaminoglycans with molecular weights ranging from 5 to 30 kD (mean, 15 kD). It is strongly acidic secondary to its high content of sulfate and carboxyl groups. Heparin is a naturally occurring substance excreted by mast cells and basophils in the process of clot formation. Standard, unfractionated heparin is derived commercially from porcine gut mucosa or bovine lung tissue. Heparin acts at multiple points within the coagulation system. Its major anticoagulant effect is via interaction with antithrombin III, leading to the inactivation of factor Xa and subsequent inhibition of the conversion of prothrombin to thrombin. Heparin further inhibits coagulation by inactivating thrombin, preventing the conversion of fibrinogen to fibrin. Heparin also prevents stable fibrin clot formation through the inhibition of fibrin stabilization factor. Heparin has no fibrinolytic activity and therefore does not lyse existing clots.
TABLE 13.1
Vascular Pharmacology
| Medication | Examples/Brand Names | Mechanism of Action | Metabolism | Half-Life | Side Effects | Dosage |
|---|---|---|---|---|---|---|
| Anticoagulants | ||||||
| Unfractionated heparin | Heparin |
|
Liver | 1.5 h |
|
|
| Low-molecular-weight heparin | Enoxaparin (Lovenox) |
|
Liver | 4.5–7 h |
|
|
| Warfarin | Coumadin |
|
Liver | 20–60 h |
|
|
| Direct thrombin inhibitors | Lepirudin (Refludan) |
|
Renal | 1.3 h |
|
0.15 mg/kg per hour IV, monitor aPTT |
| Desirudin (Iprivask) | Renal | 3 h | Anemia | 15 mg SQ q 12 h | ||
| Bivalirudin (Angiomax) | Plasma | 25 min | 0.2–0.3 mg/kg per hour IV, monitor ACT | |||
| Argatroban | Liver | 39–51 min | 2 mcg/kg per minute IV, monitor aPTT | |||
| Dabigatran (Pradaxa) | Liver | 12–17 h | 150 mg PO BID, no routine monitoring Adjust dose for renal impairment |
|||
| Factor Xa inhibitors | Fondaparinux (Arixtra) |
|
Renal | 17–21 h |
|
|
| Rivaroxaban (Xarelto) | Liver | 7–11 h | ||||
| Apixaban (Eliquis) | Liver | 17–21 h |
|
|||
| Edoxaban (Savaysa) | Renal | 10–14 h |
|
|||
| Antiplatelet Agents | ||||||
| Aspirin | Bayer Aspirin, Ecotrin |
|
Gut and plasma (ASA), liver (Salicylate) | 20 min |
|
|
| Thienopyridines | Clopidogrel (Plavix) |
|
Liver | 8 h |
|
75 mg PO QD |
| Ticlopidine (Ticlid) | Liver | 7.9–12.6 h | Neutropenia | 250 PO BID | ||
| Prasugrel (Effient) |
|
Liver | 7 h | Clopidogrel has fewer side effects than ticlopidine | 5–10 mg PO QD | |
| Glycoprotein IIb/IIIa inhibitors | Abciximab (Reopro) |
|
Unknown | 10–30 min | Thrombocytopenia Bleeding |
0.125–10 µg/kg per minute IV |
| Eptifibatide (Integrilin) | 2.5 h | 1–2 µg/kg per minute IV | ||||
| Tirofiban (Aggrastat) | 2.0 h | 0.1 µg/kg per minute IV | ||||
| ADP analogs | Ticagrelor (Brillanta) |
|
Liver | 9 h |
|
|
| PAR-1 inhibitors | Vorapaxar (Zontivity) |
|
Liver | 8 days | Bleeding |
|
| Medical Treatment of Claudication | ||||||
| Pentoxifylline | Trental |
|
Liver | 0.4–16 h |
|
|
| Cilostazol | Pletal |
|
Liver | 11–13 h |
|
|
| Reversal of Anticoagulation | ||||||
| Heparin reversal | Protamine Sulfate |
|
|
|
|
|
|
|
|
Renal | 10.3 h | Headache Hypersensitivity |
5 g IV |
| Thrombolytics | ||||||
| Tissue plasminogen activators | Alteplase |
|
Renal | 72 min |
|
|
| Reteplase (Retavase) | Renal | 13–16 min | STEMI: 10 units IV ×2 separated by 30 min | |||
| Tenecteplase (TNKase) | Liver | 90–130 min | STEMI: weight-based dosing. 30–50 mg IV ×1 | |||
BID, Twice daily; CHF, congestive heart failure; PO , per os (by mouth); QD, once daily; SC, subcutaneous; STEMI, ST-elevation myocardial infarction.
Heparin's onset of action is immediate with intravenous injection. It can also be administered subcutaneously. The response to heparin is monitored by measuring the activated partial thromboplastin time (aPTT) and activated clotting time (ACT). An aPTT 1.5 to 2.5 times normal has been shown to prevent recurrent thromboembolism. Weight-adjusted nomograms have been shown to be useful in dosing.
The anticoagulant activity of heparin varies greatly among patients. The heterogeneous clinical response is primarily due to the nonspecific binding of heparin to variable concentrations of plasma and cellular proteins, limiting heparin's bioavailability. This leads to marked variability of the anticoagulant response. There also appear to be natural inhibitors of heparin that can be released by sites of active thrombus. Further, the biophysical limitations of the large heparin–antithrombin III complex can block receptors on thrombin to heparin cofactor 2, limiting heparin's effectiveness.
Clinical use.
Heparin is indicated for intraoperative anticoagulation in vascular and cardiac surgery, for the prophylaxis and treatment of deep venous thrombosis, for the prevention of pulmonary embolism in surgical patients, and in patients with atrial fibrillation and embolization.
Adverse reactions.
Heparin therapy is associated with increased risk of bleeding. It also can cause skin lesions, including papules, plaques, and necrosis. Heparin therapy can lead to hypoaldosteronism, priapism, and osteoporosis. Thrombocytopenia is a known complication of heparin administration. Heparin-induced thrombocytopenia (HIT) can lead to thromboembolic complications, including skin necrosis, extremity gangrene, myocardial infarction, pulmonary embolism, and stroke.
Heparin-induced thrombocytopenia.
Two major forms of HIT are recognized. Type I HIT is an early-onset, benign, reversible thrombocytopenia with no associated platelet antibodies. It is non-immune mediated and is usually self-limited without complications. Type II HIT is a more serious immune-modulated thrombocytopenia. It is caused by platelet IgG antibodies that target platelet factor 4, a heparin binding protein, leading to platelet activation. The activation of platelets and endothelium and neutralization of heparin all contribute to a highly thrombogenic state. Patients with type II HIT have a high risk of developing thrombotic complications. Fortunately, most patients who develop HIT antibodies do not develop thrombocytopenia or thrombosis. Furthermore, almost all patients who develop mild to moderate thrombocytopenia during the first 4 days of heparin treatment do not have antibodies. Type II HIT should be considered a clinicopathologic syndrome with a combination of thrombocytopenia and associated clinical events, including thrombosis and confirmation of platelet antibodies. The management of HIT is aimed at preventing thromboembolic complications. All heparin should be discontinued and an alternative anticoagulant initiated.
Protamine
Structure and mechanism of action.
Protamine is made up of a heterogeneous group of low-molecular-weight proteins. These proteins are rich in arginine and are strongly basic. They occur naturally in the sperm of salmon and certain other fish species. The mechanism of action for heparin reversal is through electrostatic bonding. Heparin is highly acidic and forms a strong bond with the highly basic protamine molecules, forming an inactive complex.
Clinical use.
Protamine is used clinically as a heparin antidote. When administered alone, protamine has an anticoagulant effect similar to that of heparin. However, in the presence of heparin, it forms a stable salt, and the anticoagulant activity of both is lost. Protamine has a rapid onset of action; within 5 minutes of administration, it begins to neutralize heparin.
Adverse reactions.
Too rapid administration can have serious side effects, including hypotension and anaphylaxis. Decreased blood pressure, pulmonary hypertension, shortness of breath, flushing, and urticaria have all been associated with rapid administration. Protamine should be administered slowly over 10 minutes, with a goal of 1 mg of protamine to neutralize every 90 units of heparin. Further dosing should be guided by coagulation studies. Severe allergies have been well documented, causing transient systemic hypotension, anaphylaxis, and severe pulmonary vasoconstriction. Patients with risk factors for a protamine reaction include those with fish allergies, vasectomy, and prior protamine exposure, including protamine insulin-dependent diabetics.
Low-Molecular-Weight Heparins
Structure and mechanism of action.
Low-molecular-weight heparins (LMWHs) are collections of heparin molecules that have significantly lower molecular weights than standard, unfractionated heparin. LMWHs are derived from unfractionated heparin via chemical or enzymatic depolymerization. This produces fragments one-third the size of heparin, with mean molecular weights of 4 to 5 kD (range, 1 to 10 kD). Similar to unfractionated heparin, LMWHs are heterogeneous in terms of both molecular size and anticoagulant activity. The LMWHs have distinct differences from standard heparin. LMWHs have reduced ability to catalyze the inactivation of thrombin, because the smaller fragments cannot bind to thrombin. However, LMWHs retain the ability to inactivate factor Xa. There is a reduction in nonspecific protein binding and subsequent improved predictability in dose-response relationships. LMWHs have an increased half-life compared with standard heparin. This is thought to be secondary to reduced macrophage binding. Similarly, there is reduced binding to platelets and a decrease in the incidence of HIT. LMWHs also have been associated with a reduction in bone loss compared with standard heparin.
Clinical use.
The LMWHs have been examined extensively in the prevention of deep venous thrombosis in patients undergoing major abdominal surgery or knee and hip replacement surgery, and in patients with restricted mobility. LMWHs have also been investigated for the treatment of acute deep venous thrombosis and pulmonary embolism. LMWHs are used in patients with ACS and unstable angina. The advantages of LMWHs over standard heparin are longer plasma half-life and a more predictable anticoagulant response, allowing for simple dosing and decreasing the need for laboratory monitoring. LMWHs are also commonly used to bridge patients to oral warfarin therapy.
Adverse reactions.
Adverse reactions to LMWHs are similar to those associated with standard heparin. Bleeding, ecchymosis, and thrombocytopenia can all occur with LMWH administration. The incidence of HIT is decreased compared with standard heparin, but LMWHs can cause HIT, and patients should be monitored for this complication.
Warfarin
Structure and mechanism of action.
Warfarin is a coumarin derivative that produces an anticoagulant effect through the inhibition of vitamin K–dependent coagulation factors (II, VII, IX, X) and the anticoagulant proteins C and S. Warfarin interferes with the conversion of vitamin K into a 2,3-epoxide. Vitamin K is an essential cofactor for post-ribosomal synthesis of clotting factors, acting through the carboxylation of glutamine residues in the protein. Carboxylation promotes binding of vitamin K–dependent coagulation factors to phospholipid surfaces. Coumarins specifically block vitamin K epoxide reductase, preventing the carboxylation of the factors rendering them inactive. The vitamin K antagonists (VKAs) also inhibit carboxylation of the regulatory anticoagulant proteins C and S.
Warfarin is a racemic mixture of two optically active isomers. Absorption from the gastrointestinal tract is rapid, reaching maximal plasma levels within 90 minutes. Warfarin has a half-life of 36 to 42 hours. Response is variable owing to certain genetic factors, drug interactions, various disease states, and diet. The anticoagulant effect can be overcome by low doses of vitamin K 1 , as vitamin K 1 bypasses vitamin K epoxide reductase. Warfarin anticoagulation is monitored via measurement of the prothrombin time (PT). The PT reflects the depression of the vitamin K–dependent factors. PT measurement is laboratory dependent, and therefore the international normalized ratio (INR), a calibration model for reagent thromboplastins used in measuring the PT, was first proposed by Kirkwood in 1983, and soon thereafter was adopted by the World Health Organization as the international PT standardization scheme. It has subsequently become the standard for monitoring the effect of anticoagulant therapy with warfarin.
Clinical use.
Warfarin is indicated for the prophylaxis or treatment of venous thrombosis and thromboembolism. It is also indicated for the prophylaxis or treatment of the thromboembolic complications associated with atrial fibrillation and cardiac valve replacement. Warfarin has been shown to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
Warfarin has been studied in terms of its usefulness in promoting the patency of infrainguinal bypass grafts. Although some studies suggest improved patency of infrainguinal bypass grafts with warfarin or a combination of warfarin and aspirin, the American College of Chest Physicians 8th Edition Guidelines for Antithrombotic Therapy for Peripheral Artery Occlusive Disease recommends against long-term anticoagulation in general for extremity reconstructions. The guidelines recommend VKAs not to be routinely used for infrainguinal vein bypass, except in those patients at high risk of bypass occlusion and limb loss where VKAs plus aspirin is recommended. For infrainguinal prosthetic bypass, VKAs are not recommended to be used routinely. These conclusions are based on small improvements in patency in the face of relatively high rates of bleeding complications.
Adverse reactions.
Warfarin therapy is associated with an increased risk of hemorrhagic complications. It also can cause necrosis and gangrene of skin or other tissues. It should be used with caution in patients with HIT because it can lead to increased thrombotic complications early in the treatment of HIT.
Direct Thrombin Inhibitors
The direct thrombin inhibitors are small molecules that act directly at the active site of thrombin, without the use of an intermediate such as antithrombin III with heparin. There are five direct thrombin inhibitors currently available for clinical use: lepirudin, desirudin, bivalirudin, argatroban, and dabigatran.
Thrombin is the central enzyme in hemostasis. It is a serine protease that catalyzes the conversion of fibrinogen to fibrin. In addition, thrombin serves many other roles, including the activation of various coagulation factors, platelets, smooth muscle cells, fibroblasts, and endothelium. Thrombin is chemotactic, stimulates secretion of vasoactive proteins from platelets and inflammatory cells, and plays a role in angiogenesis and restenosis.
Antithrombin III, the major regulator of thrombin, forms an irreversible complex with thrombin to block its active site. For years, this has been the main target for thrombin inhibition and anticoagulation via heparin. However, the use of heparin is limited by several major factors: (1) the development of HIT; (2) heparin's inability to penetrate clot, leading to the release of active thrombin from clots; and (3) the variable anticoagulant response, owing to heparin's propensity to bind to plasma proteins. The rationale for the development of direct thrombin inhibitors was to create a small molecule with site-specific thrombin inhibition. With an increased understanding of the detailed molecular structure of thrombin, site-specific agents have been developed with a high specificity for thrombin.
Clinical use.
Direct thrombin inhibitors have been studied in the treatment of HIT with thrombosis; the treatment of acute coronary events; and the prevention and treatment of deep venous thrombosis, pulmonary embolism, and stroke.
Hirudin.
Hirudin, the first direct thrombin inhibitor, was originally isolated from the salivary gland of the medicinal leech (Hirudo medicinalis) after it was noted that leech saliva had anticoagulant properties. It is now produced via recombinant technology as lepirudin and desirudin. It is a 65– to 66–amino acid polypeptide. The amino terminus forms a tight bond with thrombin's active site, and the carboxy terminus binds to the thrombin exosite-1 (fibrinogen binding site). Peak plasma levels are reached after parenteral administration in 20 to 30 minutes. Hirudin is rapidly cleared by the kidneys, having a half-life of 1 to 3 hours. Some hepatic excretion also occurs but is not clinically significant. Hirudin should not be used in patients with renal failure, as no specific antidote exists, should overdosage occur.
Bivalirudin.
Bivalirudin is a recombinant protein based on hirudin. It is a 20–amino acid peptide that interacts with the active site of thrombin. It has a short half-life of 25 minutes. In contrast to hirudin, renal excretion is not the major route of excretion.
Argatroban.
Argatroban is a synthetic, small-molecule arginine derivative that interacts only with the active site of thrombin. It is metabolized by the liver, with a half-life of 45 minutes. Dose reduction may be necessary in patients with liver dysfunction. The anticoagulant effect can be monitored with the aPTT or ACT.
Melagatran/Ximelagatran.
Melagatran and Ximelagatran (its prodrug) were the first oral direct thrombin inhibitors. Although initial studies were promising for the use of Ximelagatran, it has since been removed from clinical investigation due to significant hepatotoxicity.
Novel Oral Anticoagulants
The term novel oral anticoagulant (NOAC) has been used to describe a series of medications that have come to market within the last decade that achieve their anticoagulant effect by working at points in the coagulation cascade, other than those targeted by traditional anticoagulants such as warfarin and heparin. The primary benefits of these medications over traditional anticoagulants are their ability to be administered orally and the ability to achieve a consistent degree of anticoagulation with standardized dosing rather than with monitored titration. In addition, the metabolism of these medications is not influenced by dietary intake, such as in the case of warfarin.
These medications also have characteristics that could be considered drawbacks when compared with more traditional anticoagulants. They have relatively short half-lives, and their effect can therefore be interrupted with missed doses. In addition, there are no antidotes to reverse their effects in the case of bleeding or need for emergent surgery or invasive procedure, although prothrombin complex concentrates (PCCs) have been used for this purpose with mixed results. The one exception to this rule is dabigatran, which can be counteracted by the recently released idarucizumab. The cost of NOACs is also significantly higher than traditional anticoagulants that are available as generic formulations. As such, these medications are not seen as replacements for traditional anticoagulant medications, but rather alternatives to be considered and used under appropriate circumstances.
Dabigatran
Structure and mechanism of action.
Dabigatran etexilate is a synthetic, nonpeptide, direct thrombin inhibitor that inhibits both circulating and clot-bound thrombin and lowers thrombin-stimulated platelet aggregation. It is rapidly absorbed from the gut. Peak concentrations occur approximately 1 hour after oral administration, although when taken with a high-fat meal, they are slowed to approximately 3 hours. The drug is mainly renally excreted and has a half-life of 12 to 17 hours. Renal impairment can increase serum concentrations of dabigatran. The anticoagulation effect is quite stable and monitoring is not required, which makes this drug an appealing alternative to warfarin.
Idarucizumab is a recently approved reversal agent reversal agent for dabigatran to be used in circumstances such as life-threatening bleeding and emergency surgery. Alternatively, PCC can also be administered to reduce dabigatran's efficacy, or the medication can be removed from the bloodstream via hemodialysis. Co-administration of dabigatran with other P-glycoprotein transporter substrates such as Rifampin decreases serum concentrations of dabigatran and may lower its effectiveness. P-glycoprotein inhibitors such as ketoconazole may increase serum concentrations.
Clinical use.
Dabigatran has been initially Food and Drug Administration (FDA) approved in the United States for prevention of thromboembolic stroke in patients with nonvalvular atrial fibrillation. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial studied 18,113 patients with atrial fibrillation considered high risk for stroke and over a median of 2 years of follow-up found a decrease in the rate per year of stroke or systemic embolism with dabigatran compared to warfarin (1.54% vs. 1.71%, P < .05). In 2014 dabigatran was approved for treatment of venous thromboembolism (VTE) in patients who have been treated with a parenteral anticoagulant for 5 to 10 days, and to reduce the risk of recurrent VTE in patients who have been previously treated. This approval was based on the results of four global clinical trials: RE-COVER, RE-COVER II, RE-MEDYSM, and RE-SONATE. In 2015 dabigatran received FDA approval for prophylaxis against VTE in patients who have undergone hip replacement surgery based on the results of the RE-NOVATE and RE-NOVATE II clinical trials.
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