Article, Toxicology

Time to individualize duration of parenteral anticoagulation in pulmonary thromboembolism?

Gheshlaghi Farzad MD

Department of Clinical Toxicology and Forensic Medicine

School of Medicine Isfahan University of Medical Sciences

Isfahan, IranIsfahan Clinical Toxicology Research Center

Isfahan University of Medical Sciences

Isfahan, Iran E-mail address: [email protected]



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Time to individualize duration of parenteral anticoagulation in pulmonary thromboembolism?

To the Editor,

Modeling suggests that more than 900 000 incident or recurrent venous thromboembolism events occur annually in the United States, of which approximately one third are fatal; 30-day pulmonary thromboembolism (PTE) survival is 59.1% [1]. Drawbacks of the current PTE protocol were pointed out recently [2]. Contemporary guidelines for initial anticoagulants in PTE are based on only 2 relatively old (N20 years) studies: one in DVT and the other in VTE patients (some of them having PTE) [2-4]. It is questionable if half of the single, old study in PTE is enough to make generalization to all PTE patients today.

Moreover, there are a few additional possible drawbacks of the current protocol:

  1. It was proved that heparin efficacy during the first day is very important [5]. Thus, giving oral anticoagulant (OAC) from the first day may be somewhat counterproductive (at least theoretically) because of well-known prothrombotic action of warfarin in the first days of administration. Warfarin inhibits proteins C and S early (24-48 hours), leading to a transient hypercoaguable state, followed by a full anticoagulant affect–by inhibition of factors II, VII, IX, and X [6].
  2. The risk of bleeding is already greatest during the first treatment weeks [7], and there is a higher probability of

warfarin overdosing early in its administration [8]. It is more difficult to antagonize the anticoagulant effect of both parenteral and OAC, as compared with only parenteral one. Warfarin’s slow offset of action is also troublesome [9,10]. Thus, early administration of OAC both increases the bleeding risk and complicates treatment if hemorrhage occurs.

  1. Besides, there may be a problem if supratherapeutic international normalized ratio (eg, international normal- ized ratio = 5) is achieved, for example, on third day– should one stop heparin before the day 5?
  2. In addition, later start of OAC therapy makes vena cava filter implantation less risky, if indicated.
  3. Starting OAC on the first day may be harmful if patient’s symptoms and findings get worse to the level of life threat and the “escalation of therapy” (eg, fibrinolytic) becomes necessary.

We propose the evaluation of the option to prolong (more efficient) parenteral anticoagulant in PTE patients with higher risk and unsatisfactory response to already-applied parenteral anticoagulant therapy. Rationale:

  1. It is possible to risk-stratify PTE patients.
  2. Multiple imaging and other modalities are now available for the objective evaluation of the effects of parenteral anticoagulant in PTE.
  3. The principle of therapy evaluation is generally accepted in medicine.
  4. Residual thrombosis should be minimized/eliminated in VTE patients because it contributes to both recurrent VTE and worse prognosis. Patients with (vs without) residual venous thrombosis had a 6.5-fold to 24.9-fold increase in the risk of a recurrent VTE [8,11]. Accord- ingly, we should try to eliminate thrombi as soon and as safely as possible.
  5. To do this, it is logical to apply stronger anticoagulants longer, and parenteral anticoagulants are more effective than OAC. Namely, heparin not only acts more rapidly than OAC, but it also has a better antithrombotic effect [12-14]. Moreover, low-molecular-weight heparin (LMWH) is preferred to unfractionated heparin (UFH) for the initial treatment of acute nonmassive PTE antithrombotic therapy for Venous thromboembolic disease– American College of Chest Physicians Guide- lines (8th Edition) recommendation grade 1A) [15]. In addition, European Society of Cardiology Guidelines suggested for acute non-high-risk PTE, without severe renal dysfunction, LMWH or fondaparinux, given subcutaneous (SC), over UFH [16]. Furthermore, Cochrane database review found that LMWH, compared with UFH, significantly reduced the incidences of recurrences, major hemorrhages, and overall mortality in VTE at follow-up [17]. Thus, in VTE LMWHs have better risk/benefit ratio than UFH, which is more efficient than OAC.

We believe that it is worth checking in randomized controlled trial(s) that an individual patient, at low risk for bleeding and for HIT, should receive parenteral anticoagu- lant longer (until objective evidence of substantial improve- ment) if his/her:

  1. cardiovascular status is worse at baseline, the Pulmonary Embolism Severity Index (PESI) is higher, and clinical course is without satisfactory improvement in first days.
  2. Thrombus burden is larger, and its localization is more central.
  3. Right ventricle is larger, and pulmonary artery pressure is higher.
  4. Biomarkers’ concentrations (brain natriuretic peptide, High-sensitive troponin, D-dimer) are higher.
  5. Risk for recurrence is higher. It is very important that “VTE begets VTE,” that is, patients with residual VTE have more often recurrence of VTE [18-21]. Residual thrombosis is frequent in PTE: after months of follow-up, it was found in 70.9% of patients [22].

Which parenteral anticoagulant should be administered? Recent meta-analysis demonstrated that LMWH had better risk/benefit ratio than UFH in VTE [17]. Because LMWHs were shown to be more efficacious than UFH [11], which was more effective than OAC [12-14], it is very probable that LMWHs are more potent anticoagulants in comparison with OAC [23,24]. A meta-analysis of 7 studies in VTE (1379 patients) found reductions of 34% in VTE recurrence (statistically nonsignificant), 66% in hemorrhages (statisti- cally highly significant), and 55% in major bleeds (statisti- cally nonsignificant) in favor of LMWHs vs OAC (for

>=3 months) [25,26]. Similarly, a Cochrane Library review

demonstrated that OAC and LMWH were equally efficient in the secondary prevention of VTE but that LMWHs were possibly safer [26,27]. In addition, Pooled analysis of 5 studies showed 34% better efficacy (Pb .0001) of LMWH vs OAC in complete recanalization of thrombosed veins [24].

Why fondaparinux can be suggested for prolonged parenteral anticoagulant therapy? There are at least 2 reasons:

(1) minimal or no chances for HIT and osteoporosis (because fondaparinux binds only to antithrombin) and (2) once daily, fixed dose administration [16,25].

Taken together, we pledge to match the intensity of (anticoagulant) therapy (by adjusting duration of stronger parenteral anticoagulant) with the severity of the disease (PTE).

What we suggest is a randomized controlled trial to test conventional vs new protocol with individualized duration of parenteral anticoagulant therapy in nonmassive PTE pa- tients: fondaparinux (or LMWH), which is probably more efficacious than warfarin (and fondaparinux does not cause HIT), should be administered until satisfactory improvement in symptoms, objective evidence of thrombus burden diminishing, and control of the hypercoagulability is achieved; then, we may proceed with the overlap with OAC.


This work has been supported by the Serbian Ministry of Education and Science, grant no. 175092.

Goran P. Koracevic MD, PhD

Department of Cardiology Clinical Centre and Medical Faculty

University of Nis

Nis, Serbia E-mail addresses: [email protected]

[email protected]



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Hyperalgesic acetabular fracture treated by transversus abdominis plane block in the EDB

To the Editor,

We considered the critical situations using transversus abdominis plane block (TAP) for analgesia described by Herring et al [1]. We used TAP in an original indication: hyperalgesic, opiate-resistant acetabular fracture analgesia.

In the emergency department, a 21-year-old woman with major trauma was admitted after a car crash. She had no significant medical history. She had stable pelvic fracture with left acetabular, right iliac wing and right ischium

fractures, and stable spleen hematoma. Simple immobiliza- tion was indicated. She had severe left hip pain. It was 90/100 on the numerical rating scale (NRS). A Multimodal analgesia was started with paracetamol, nefopam, and morphine association. A sentinel CPA (morphine sulfate) was also installed. After morphine (12 mg), the patient presented adverse effects: drowsiness and bradypnea without effective analgesia (NRS, 70/100). On day 2, a left ultrasound-guided subcostal TAP block was performed. We injected 15 mL of lidocaine 2% and introduced a catheter in the injection space (Figure). It allowed sufficient analgesia (NRS, 10/100) after 30 minutes. We maintainED analgesia by continuous 0.2% ropivacaine infusion. Morphine consumption was 8 mg (CPA) on day 1 (before TAP catheter insertion) and only 2 mg on day 2, used for posterior pelvic pain preceding nursing mobilizations. The patient was discharged on day 4 in the orthopedic ward. Transversus abdominis plane block catheter was removed on day 5. After catheter removal, hip pain scored NRS 30/100 was controlled by multimodal analgesia. Epidural anesthesia could be adapted for pain control, but strict decline induced lateralization difficult to realize epidural procedure. That is why we proposed TAP. This technique induces thoracolumbar nerve blockade (T7 to L1), which supply anterolateral abdominal wall innervation [2]. Very few complications are described for this technique [3].

The Analgesic efficacy of the TAP has been demonstrated in prospective randomized trials compared with placebo, in different surgical procedures such as abdominal surgery, hysterectomy, retropubic prostatectomy, cesarean delivery, and laparoscopic cholecystectomy [2]. It showed as well good results in acute pancreatitis [4]. Catheter insertion is possible to provide bolus as an effective alternative to epidural infusion to provide postoperative analgesia after upper abdominal surgery [5]. Transversus abdominis plane block is efficient for parietal and intraabdominal pain [6], but only few reports are presented on pelvic pain. Chiono et al

[7] presented a study on analgesia with TAP in Iliac crest bone graft: 20 minutes after injection, 62.5% of the patients reported complete anesthesia, and 34% hypoesthesia. At 18 months, 80% of patients did not complain about pain at

B Conflict of interest: none. Figure TAP catheter and posttrauma skin pelvic lesion.