Dosing Intensity of Anticoagulants for the Prevention and Treatment of Venous Thromboembolism and the Prevention of Stroke in Atrial Fibrillation: Why is There a Difference?

Results of clinical trials with the old and newer anticoagulants support the recommendation that lower doses (resulting in lower anticoagulant exposure) should be used to prevent venous thrombosis rather than to treat established venous thrombosis or to prevent embolic stroke in atrial fibrillation (AF). In this brief commentary, we will review the evidence for using different dosing regimens for each of the three indications ([Table 1]) and offer potential explanations for these dosing differences.

Table 1 Dosing of anticoagulants for VTE prevention, acute VTE treatment, and stroke prevention in atrial fibrillation

Anticoagulants	VTE prevention	Acute VTE treatment	Stroke prevention in AF
Unfractionated heparin	5,000 IU subcutaneously q8h or q12h	IV bolus 5,000 IU (or 80 IU/kg) followed by 20 IU/Kg/h adjusted according to aPTT	–
Dalteparin	5,000 IU once daily	100 IU/kg twice daily or 200 IU/kg once daily	–
Enoxaparin	30 mg twice daily or 40 mg daily	1 mg/kg twice daily or 1.5 mg/kg once daily	–
Tinzaparin	50–75 IU/kg	175 IU/kg once daily	–
Fondaparinux	2.5 mg once daily	5 mg once daily for weight <50 kg 7.5 mg once daily for 50–100 kg 10 mg once daily for >100 kg
Dabigatran[a]	110 mg within 1–4 h after surgery then 150 mg or 220 mg daily	150 mg twice daily after 5–10 d of parenteral anticoagulant	150 mg twice daily
Apixaban[b]	Apixaban 2.5 mg twice daily	10 mg twice daily for 7 d then 5 mg twice daily	5 mg twice daily
Rivaroxaban[c]	Rivaroxaban 10 mg once daily	15 mg twice daily for 21 d then 20 mg once daily	20 mg once daily
Edoxaban[d]	–	60 mg once daily after 5–10 d of parenteral anticoagulant	60 mg once daily

Abbreviations: AF, atrial fibrillation; aPTT, activated partial thromboplastin time; IU, international units; IV, intravenous; VTE, venous thromboembolism.

^a Dabigatran: For patients ≥80 years or with high bleeding risk—110 mg twice daily.

^b Apixaban: For AF—2.5 mg twice daily for patients at least 2 of the following: ≥80 years, ≤60 kg, or with creatinine ≥1.5 mg/dL.

^c Rivaroxaban: For AF—15 mg daily with creatinine clearance 15–50 mL/min.

^d Edoxaban: 30 mg daily for one of the following: creatinine clearance 15–50 mL/min, ≤60 kg body weight, or concurrent use of potent P-glycoprotein inhibitors.

Before the 1970s, the use of anticoagulants to prevent and treat thrombosis was inconsistent and the dose used was left to the whim of the treating physician.[1] The situation changed in the early 1970s when VJ Kakkar showed that low doses of unfractionated heparin (UFH) given by subcutaneous injection (5,000 units twice or three times daily) were effective in preventing venous thromboembolism (VTE),[2] [3] and when Basu et al reported that the risk of recurrent VTE in patients treated with continuous intravenous UFH was increased when the anticoagulation intensity, as measured by the activated partial thromboplastin time (aPTT), fell below 1.5 times the control value.[4] Both reports changed clinical practice, although the study by Basu et al was not well designed by current standards. Since then, several well-designed clinical trials with a variety of anticoagulants have confirmed the observation that higher doses of anticoagulants are required to treat than to prevent VTE.

The need for higher doses of UFH to treat than to prevent VTE was first demonstrated in 1980 when low-dose UFH, which was highly effective in preventing VTE, was shown to be ineffective at preventing the extension of acute deep vein thrombosis.[5] [6] Likewise, based on the results of phase III studies, the recommended and approved doses of low molecular weight heparins, fondaparinux, dabigatran, apixaban, and rivaroxaban were also found to be lower for the prevention than the treatment of VTE ([Table 1]). Warfarin was an exception since it was used with an identical intensity for the prevention and treatment of VTE. However, when used for the prevention of postoperative VTE, its full anticoagulant effect was not manifest for 4 to 6 days after surgery.[7] Therefore, its anticoagulant effect was of low intensity in the early postoperative period. The adequacy of a lower international normalized ratio (INR) level was supported by the study by Levine et al which showed that warfarin at a targeted INR of 1.3 to 1.9 was effective in preventing VTE in patients with breast cancer who were receiving chemotherapy.[8]

Anticoagulants were generally not recommended for stroke prevention in patients with nonvalvular AF until the results of clinical trials comparing warfarin with no treatment were published in the early 1990s.[9] These randomized trials showed that warfarin at an intensity equivalent to an INR of 2.0 to 3.0 was highly effective in reducing the risk of stroke in nonvalvular AF. Importantly, results of a subgroup analysis of one trial and of case-control studies suggested that the efficacy of warfarin was reduced when the INR fell below 2.[10] In one of these studies, the odds of stroke doubled at an INR of 1.7 and tripled at an INR of 1.5 compared with an INR of 2.[11] Further, based on results of phase III studies, the approved doses of the direct oral anticoagulants (DOACs) for the prevention of stroke and systemic embolism in patients with AF are also similar to those used for the acute (early) treatment of VTE and are approximately twofold higher than those recommended for the prevention of VTE. ([Table 1]).

In summary, with no exceptions, the dose and intensity of anticoagulation is less for the prevention of VTE than it is for the acute treatment of VTE and the prevention of stroke in AF.

Why should this be? We hypothesize that the higher anticoagulant intensity required to treat VTE than to prevent VTE can be explained by the highly thrombogenic nature of acute thrombi, likely resulting from the combined effects of fibrin bound thrombin and prothrombinase bound factor Xa and other activated coagulation factors; a notion that is consistent with the observation that the prophylactic dose of DOACs is as effective as therapeutic dose when the acute phase of VTE is over and treatment is aimed at secondary prevention of VTE. The reason for the higher anticoagulation intensity requirement to prevent embolic stroke in AF than to prevent VTE is likely the result of the more serious consequence of small emboli breaking off from an atrial thrombus than from a venous thrombus. Thus, based on human autopsy data, the diameter of the middle cerebral artery ranges from 2 to 5 mm along its course (with a mean of 3 mm) and therefore is vulnerable to obstruction by small emboli that can cause an ischemic stroke.[12] [13] In contrast, the pulmonary arterial circulation has the capacity to withstand much greater thromboembolic obstructions without untoward effects. The knowledge that the dose required for the prevention of embolic stroke in AF is about twice as high as that required to prevent VTE could have practical importance in the clinical evaluation of newer anticoagulants such as the factor XIa inhibitors. Typically, for practical reasons, the optimal dose of a new anticoagulant is first determined in phase III studies in VTE prevention in patients undergoing major orthopaedic surgery. The knowledge of the optimal dose for VTE prevention can be used to inform on the range of doses selected for testing in phase II studies for VTE treatment or stroke prevention in AF.

Publication History

Article published online:
18 June 2024

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