, Benjamin Hohlfelder2 and Samuel Z. Goldhaber3
(1)
Cardiovascular Division, Harvard Medical School Brigham and Women’s Hospital, Boston, Massachusetts, USA
(2)
Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, Massachusetts, USA
(3)
Thrombosis Research Group, Harvard Medical School Brigham and Women’s Hospital, Boston, Massachusetts, USA
Abstract
Prompt therapeutic-level anticoagulation is the cornerstone of treatment for venous thromboembolism (VTE). Options for anticoagulation in VTE include unfractionated heparin, low-molecular-weight heparin, fondaparinux, argatroban, bivalirudin, warfarin, and the non-vitamin K oral anticoagulants (NOACs) rivaroxaban, dabigatran, apixaban, and edoxaban. The NOACs represent a major advance in anticoagulation for VTE with superior safety and equivalent efficacy compared with warfarin.
Keywords
AnticoagulationHeparinLow-molecular weight heparinNOACsNon-vitamin K oral anticoagulantsWarfarinSelf-Assessment Questions
1.
Which of the following anticoagulation regimens for VTE treatment is correct?
(a)
Dalteparin 200 units/kg subcutaneously once daily in a patient with advanced breast cancer and acute pulmonary embolism (PE).
(b)
Dabigatran 150 mg orally twice daily in a patient with subclavian vein thrombosis associated with a hemodialysis access catheter.
(c)
Warfarin with a target International Normalized Ratio (INR) range of 2–3 in a patient receiving total parenteral nutrition (TPN) for chronic pancreatitis and malabsorption and suffered lower extremity deep vein thrombosis (DVT).
(d)
Enoxaparin 1 mg/kg subcutaneously twice daily in a patient with a remote history of heparin-induced thrombocytopenia who presents with acute PE.
2.
Which of the following statements about use of NOACs for treatment of VTE is correct?
(a)
NOACs are comparable to warfarin with regard to cost burden to the patient.
(b)
NOACs have been proven to be non-inferior with regard to efficacy and superior with regard to bleeding complications compared with warfarin.
(c)
NOACs are preferred in patients who have difficulty remembering to take their medications as directed.
(d)
Apixaban and edoxaban are administered as completely oral monotherapy with a loading dose followed by a maintenance dose.
3.
Which of the following strategies for treating anticoagulant-associated major bleeding is not correct?
(a)
Protamine for intravenous unfractionated heparin
(b)
Prothrombin complex concentrate for warfarin
(c)
Hemodialysis for apixaban overdose
(d)
Prothrombin complex concentrate for rivaroxaban
Clinical Vignette
A 54-year-old man presented to the Emergency Department 3 weeks following L4-L5 laminectomy and fusion with acute dyspnea and right-sided pleuritic flank pain. He noted that his mobility had been limited by post-operative pain in the few weeks since hospital discharge. On physical examination, he had a heart rate of 82 beats per minute, a blood pressure of 126/78 mmHg, and an oxygen saturation of 92 % on room air. Because of his post-operative state and a high suspicion for PE, the patient proceeded directly to contrast-enhanced chest computed tomogram (CT). The study demonstrated a right lower lobe subsegmental PE (Fig. 9.1) and associated wedge-shaped pleural based opacity consistent with a pulmonary infarct (Fig. 9.2). His chest CT-determined RV diameter-to-LV diameter ratio was normal at 0.89 (Fig. 9.3). The patient was promptly administered intravenous (IV) unfractionated heparin as a bolus followed by infusion titrated to a goal activated partial thromboplastin time (aPTT) of 50–70 s and admitted to the Medical Service. His symptoms and hypoxemia improved over the subsequent 48 h. The Medical Team discussed options for oral anticoagulation with the patient who preferred an agent that did not require routine laboratory monitoring or dose adjustment. The team discharged the patient on one of the non-vitamin K oral anticoagulants.
Fig. 9.1
Contrast-enhanced chest computed tomogram (CT) demonstrating right lower lobe subsegmental pulmonary embolism (PE) (arrow) in a 54-year-old man with dyspnea and right-sided pleuritic flank pain following spine surgery
Fig. 9.2
Contrast-enhanced chest computed tomogram (CT) demonstrating a right lower lobe pulmonary infarct (arrow) in a 54-year-old man with dyspnea and right-sided pleuritic flank pain and acute pulmonary embolism (PE) following spine surgery
Fig. 9.3
Contrast-enhanced chest computed tomogram (CT) demonstrating normal right ventricular (RV) size as defined by a normal RV diameter-to-left ventricular (LV) diameter ratio (5 cm/5.6 cm = 0.89; normal ≤ 0.9) in a 54-year-old man with acute pulmonary embolism (PE) following spine surgery
Regardless of whether patients receive advanced therapy, prompt therapeutic-level anticoagulation remains the cornerstone of treatment for VTE. Currently, U.S. Food and Drug Administration-approved agents for anticoagulation in VTE include unfractionated heparin, low-molecular-weight heparin, fondaparinux, argatroban, bivalirudin, warfarin, and the non-vitamin K oral anticoagulants (NOACs) rivaroxaban, dabigatran, apixaban, and edoxaban. The NOACs, also known as target-specific oral anticoagulants (TSOACs) or direct oral anticoagulants (DOACs), represent a major advancement in anticoagulation for VTE with strong safety and efficacy performance in their respective randomized controlled trials [1–6].
Parenteral Anticoagulation
Unfractionated Heparin
The majority of patients with massive or submassive VTE will initially receive unfractionated heparin administered as an IV bolus, followed by continuous infusion titrated to a goal aPTT of 2–3 times the upper limit of normal, or approximately 60–80 s. Weight-based protocols such as the modified Raschke nomogram are widely used and may more rapidly achieve therapeutic levels of anticoagulation (Table 9.1) [7, 8]. Because it can be discontinued and rapidly reversed, unfractionated heparin is the preferred anticoagulant for patients undergoing advanced therapy with fibrinolysis, catheter-based intervention, or surgery for VTE. Although unfractionated heparin is continued during fibrinolysis for acute myocardial infarction, it is withheld during the administration of systemic dose recombinant tissue-plasminogen activator (t-PA) for VTE and is not restarted until the aPTT has fallen to less than 80 s or twice the upper limit of normal [9]. The patient in the Clinical Vignette was initiated on IV unfractionated heparin as soon as the diagnosis of PE was established.
Table 9.1
A generally-accepted weight-based unfractionated heparin nomogram
Variable | Heparin dose |
|---|---|
Initial heparin dose | 80 U/kg bolus, then 18 U/kg/h |
aPTT <35 s (<1.2 × control) | 80 U/kg bolus, then increase infusion by 4 U/kg/h |
aPTT 35–59 s (1.2–1.9 × control) | 40 U/kg bolus, then increase infusion by 2 U/kg/h |
aPTT 60–89 s (2.0–2.9 × control) | No change |
aPTT 90–100 s (3.0–3.3 × control) | Decrease infusion by 3 U/kg/h |
aPTT >100 s (>3.3 × control) | Hold infusion 1 h; then decrease infusion rate by 4 U/kg/h |
Low-Molecular Weight Heparin
Low-molecular-weight heparins (LMWHs), including enoxaparin, dalteparin, and tinzaparin, offer several advantages over unfractionated heparin, including longer half-life, more consistent bioavailability, and more predictable dose response. LMWHs are dosed according to weight, administered subcutaneously, and do not require dose adjustments or laboratory monitoring under routine circumstances.
Several trials have demonstrated that LMWHs are at least as safe and effective as IV unfractionated heparin in the prevention of recurrent VTE after DVT [10–12]. A meta-analysis of randomized, controlled trials comparing LMWH therapy with IV unfractionated heparin for the treatment of DVT demonstrated a 30 % reduction in mortality and 40 % reduction in risk of major bleeding associated with LMWH use [11]. The U.S. Food and Drug Administration (FDA) has approved enoxaparin and tinzaparin for treatment of DVT as “bridge” to therapeutic oral anticoagulation. LMWHs have also been shown to be as safe and effective as IV unfractionated heparin in the prevention of recurrent VTE among patients with acute PE [13, 14].
For patients with active cancer, LMWH monotherapy without transition to oral anticoagulation is preferred over warfarin in evidence-based guideline recommendations [15, 16]. In a randomized controlled trial of 676 cancer patients, LMWH monotherapy with dalteparin halved VTE recurrence compared with warfarin (hazard ratio [HR], 0.48; p = 0.002) [17].
In contrast to unfractionated heparin, which is largely eliminated by the liver, LMWHs are cleared renally. Patients with impaired renal clearance, massive obesity, pregnancy, or unanticipated bleeding or thromboembolism despite correct weight-based dosing of LMWH may benefit from laboratory monitoring. Although the aPTT is checked to monitor the level of anticoagulation with unfractionated heparin therapy, anti-Xa levels (often called “heparin levels”) are used to determine the level of anticoagulation with LMWHs. The goal therapeutic range for anti-Xa levels is 0.5–1.0 anti-Xa IU/mL. Anti-Xa levels should be drawn 4–6 h after the second or third dose of LMWH to ensure a steady-state value. The use of anti-Xa testing has been the subject of considerable debate because the correlation of anti-Xa levels to antithrombotic effect and risk of bleeding has come into question [18, 19].
Adverse Effects of Heparin
Bleeding is the most common clinically important adverse effect of heparin therapy. Although in most cases discontinuation of heparin therapy is sufficient, protamine sulfate may be necessary to reverse the effects of heparin in the setting of life-threatening hemorrhage. Protamine sulfate is administered as a slow IV infusion in a dose of 1 mg for every 100 units of heparin administered over the preceding 4 h, up to a maximum dose of 50 mg. A potentially severe allergic reaction may occur in patients who have been exposed to Neutral Protamine Hagedorn (NPH) insulin. In general, major bleeding from the respiratory, gastrointestinal, or genitourinary tracts should not be attributed to anticoagulation alone, and an evaluation for a source of bleeding such as malignancy should be undertaken after the acute illness has resolved.
Other important potential adverse effects of heparin therapy include heparin-induced bone loss and thrombocytopenia.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent IgG antibodies directed against heparin-platelet factor 4 complex. Although bleeding is a rare complication of HIT, devastating arterial and, more commonly, venous thromboembolic complications may culminate in limb-threatening and life-threatening ischemia. Although the risk is lower with LMWHs, both unfractionated heparin and LMWHs are associated with the development of HIT. HIT must be distinguished from transient early decreases in the platelet count that frequently normalize within 3 days despite ongoing administration of heparin. A decrease in the platelet count of greater than 50 % of baseline or a new thromboembolic event in the setting of any heparin product, including heparin flushes and heparin-coated catheters, should raise concern for true HIT and lead to the discontinuation of all heparin-containing products.
A clinical scoring system that incorporates the “4T’s” can be used to evaluate patients in whom HIT is suspected: Thrombocytopenia, Timing, Thrombosis, and the absence of other more likely diagnoses (Table 9.2) [20]. Patients with a score of less than or equal to 3 have a low likelihood of HIT (<5 %). A score of 4 or 5 corresponds with an intermediate likelihood of HIT. Scores of 6 or greater indicate that HIT is likely (>80 %). HIT typically occurs within 4–14 days from initial heparin exposure but may occur earlier if the patient has been previously exposed to heparin. Clinicians should consider the diagnosis of delayed-onset HIT [21]. Anti-platelet factor 4/heparin antibody and serotonin release assay testing are the laboratory tests used to diagnose HIT. Higher levels of anti-platelet factor 4/heparin antibody are associated with increased risk of thrombosis among patients with clinically suspected HIT [22].
Table 9.2
A generally-accepted tool for assessing the probability of heparin-induced thrombocytopenia (HIT)
Points assigned for each category | |||
|---|---|---|---|
2 | 1 | 0 | |
Thrombocytopenia | >50 % platelet fall or nadir is 20 × 109/L | 30–50 % platelet fall or nadir 10–19 × 109/L | <30 % platelet fall or nadir <10 × 109/L |
Timing of onset of platelet drop or clinical sequelae | Fall between days 5–10 after initial heparin exposure, or within 1 day of heparin reexposure (if previous heparin exposure was within past 30 days) | Fall after day 10 or if timing unclear or within 1 day of heparin reexposure (if previous heparin exposure was within past 30–100 days) | Fall before day 5 and no recent heparin |
Thrombosis or other sequelae | New proven thrombosis; skin necrosis; acute systemic reaction | Progressive or recurrent thrombosis; erythematous skin lesions; suspected thrombosis (not proven) | None |
Other causes of platelet decline | None evident | Possible | Definite |
“High probability” 6–8 points | |||
“Intermediate probability” 4–5 points | |||
“Low probability” 0–3 points | |||
When HIT is confirmed or even suspected, a direct thrombin inhibitor such as argatroban or bivalirudin should be administered. Unlike bivalirudin, argatroban does not require dose adjustment for renal insufficiency. However, argatroban is hepatically cleared and should be used with caution in patients with impaired liver function. Several other pitfalls in the management of HIT must be avoided. Warfarin as monotherapy should not be used for anticoagulation because it may worsen the procoagulant state and precipitate limb gangrene. Platelet transfusions “add more fuel to the fire” and are contraindicated. Inferior vena cava filter insertion without concomitant anticoagulation can result in caval, pelvic, and lower extremity venous thrombosis. LMWHs, although less likely to cause HIT, will often cross-react with IgG antibodies once HIT has developed and may lead to worsening thrombocytopenia and thrombosis.
Fondaparinux
Fondaparinux is a synthetic pentasaccharide with anti-Xa activity approved by the FDA for the initial therapy of DVT and PE. Fondaparinux has been shown to be at least as safe and effective as enoxaparin in the initial treatment of patients with symptomatic DVT [23]. Among hemodynamically stable patients with acute symptomatic PE, fondaparinux is as safe and effective as IV unfractionated heparin [24]. Fondaparinux is administered as a once-daily subcutaneous injection in fixed doses of 5 mg for body weight less than 50 kg, 7.5 mg for body weight of 50–100 kg, and 10 mg for body weight greater than 100 kg. Fondaparinux does not require routine monitoring or dose adjustment with laboratory coagulation tests. Because it is cleared by the kidneys, fondaparinux is contraindicated in patients with severe renal impairment. In contrast to unfractionated heparin and LMWH, fondaparinux does not cause HIT. Fondaparinux at a dose of 2.5 mg once daily for 45 days has been shown to be safe and effective in the treatment of patients with acute, symptomatic superficial vein thrombosis of the lower extremities [25]. However, there is no antidote or reversal agent to manage bleeding complications.
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