Article

Importance of meta-analysis of long-term trials of low-molecular-weight heparin vs vitamin K antagonist in pulmonary embolism

Correspondence / American Journal of Emergency Medicine 31 (2013) 621630 627

Importance of meta-analysis of long-term trials of

low-molecular-weight heparin vs vitamin K antagonist in pulmonary embolism?

Numerous studies as well as meta-analyses showed that low- molecular-weight heparin (LMWH) was better than vitamin K antagonist in the long-term therapy for venous thromboem- bolism (VTE) [1-6]. This is mostly due to the recognized advantage of LMWH vs VKA in long-term VTE treatment of cancer patients [7,8]. Otherwise, long-term LMWH and VKA are believed to have similar risk/benefit ratio in VTE or pulmonary thromboembolism (PTE) patients [8]. After the exclusion of studies enrolling only cancer patients, LMWH was somewhat better: there was a 21% reduction of the risk of recurrent symptomatic VTE during treatment in favor of LMWH vs VKA; but it was statistically nonsignificant [7], whereas the risk of (major) bleeding was significantly lower in the LMWH group [5,9] or at least similar [7], which is important, indeed.

It is surprising that LMWH is not more persuasively better than VKA in long-term secondary VTE prevention in noncancer patients, knowing the advantages of LMWH generally (eg, more stable antic- oagulation) [8]. Fixed doses and very high bioavailability guarantee a stable anticoagulation with LMWH, whereas only a minority of patients remained on the therapeutic VKA range. Poor International normalized ratio control is a risk factor for recurrent VTE [7]. Admittedly, there may be another logical explanation why LMWH was not superior for long-term secondary thromboprophylaxis in com- parison with VKA; namely, all these studies were randomized, so patients were similar in almost every way, including how high their risk is (that is what randomization is made for). It is possible that LMWH had a better risk/benefit ratio in more severe noncancer VTE patients but that this advantage was diluted by the absence of advantage in low-risk patients in the same therapeutic arm (eg, LMWH arm) of the trial. By possible analogy, cancer patients have also a more severe VTE and were shown by similar analysis to benefit more from LMWH than from VKA in the long term.

Moreover, with respect to doses, there is also the nonindividua- lized approach (the same dose for VTE patients at higher and at lower risk), with a resulting dilemma; namely, long-term prophylactic LMWH doses have quite comparable results with VKA, so why should one use an intermediate or high dose? On the other hand, meta- regression analysis showed an inverse relationship between LMWH dose and the prevention of recurrence, making prophylactic LMWH doses too low for effective long-term anticoagulation [5].

Thus, as far as drug choice is concerned, it is possible that analyzing all VTE/PTE patients as a group (without separate analysis of more and less severe ones) might obscure an eventual advantage of long-term LMWH over VKA in higher-risk noncancer patients. Likewise, analyzing the LMWH dose in all VTE/PTE patients together, without dividing patients into high and low risk for VTE recurrence/death, might mask the following possibility: higher LMWH doses may be more beneficial for high-risk VTE patients, and lower doses may be superior for the low-risk patients.

We suggest analysis of the individual trials and–even better–a meta- analysis of all appropriate long-term LMWH vs VKA trials in VTE/PTE trials (eg, [10-13]) comparing patients with high vs low risk. This analysis should be performed after the exclusion of previously diagnosed (known) cancer patients to see whether other high-risk patients also benefit more from long-term LMWH vs VKA. We have objective tools to evaluate severity of PTE: the Pulmonary Embolism Severity Index (PESI) [14,15] and others (eg, the Geneva Clinical score) [16,17].

Thus, the idea is to look for a new potential subgroup (noncancer high-risk patients) in PTE/VTE long-term trials of LMWH vs VKA who

? This work has been supported by the Serbian Ministry of Education and Science (grant 175092).

may have significantly better response to LMWH (in comparison to VKA), as already demonstrated for cancer patients. If shown so, patient with high PESI score at the admission (even without cancer) may be treated with LMWH for a longer period. Moreover, patients can be reassessed later to see if something important changed (eg, symptoms, O2 saturation, electrocardiogram, echo, D-dimer) or improved [18]. It is quite in accordance with recalculation of PESI score (PESI48) [15].

Thrombolyzed PTE patients should be treated using unfractionated heparin because no other anticoagulant for acute PTE was ever tested; and consequently, this idea refers only to the nonthrombolyzed patients. Until the analysis we propose becomes available, some suggestions already exist in the literature. The first meta-analysis suggested that LMWH might be cost-effective in the long term, especially in patients at high risk of recurrence or major bleeding [19]. Furthermore, in addition to patients with cancer, it is quite reasonable to consider the following as possible indications for the long-term use of LMWHs to prevent recurrent VTE: patients with recent blood loss or active gastroDuodenal ulcer, those older than 80 years, and those exhibiting a very unstable INR and when INR measurements are not available [20].

Conclusion

It is logical to adjust the choice, intensity and duration of anticoagulant drugs to the calculated (and possibly recalculated) severity score (such as PESI) for long-term PTE therapy. A randomized clinical trial to analyze the putative advantage of LMWH as compared with VKA in noncancer high-risk PTE patients for Long-term treatment would be the best option; but it is difficult to perform, lengthy, and costly. Thus, it seems rational to perform (meta-)analysis of trials already done.

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] http://dx.doi.org/10.1016/j.ajem.2012.12.012

References

  1. Lopez-Beret P, Orgaz A, Fontcuberta J, et al. Low Molecular Weight Heparin versus oral anticoagulants in the long term treatment of deep venous thrombosis. J Vasc Surg 2001;33:77-90.
  2. Daskalopoulos ME, Daskalopoulou SS, Tzortis E, et al. Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomised trial. Eur J Vasc Endovasc Surg 2005;29:638-50.
  3. Hull RD, Pineo GF, Brant RF, et al. LITE Trial Investigators. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms. Am J Med 2007;120:72-82.
  4. Gonzalez-Fajardo JA, Martin-Pedrosa M, Castrodeza J, et al. Effect of the anticoagulant therapy in the incidence of post-thrombotic syndrome and recurrent thromboembolism: comparative study of enoxaparin versus coumarin. J Vasc Surg 2008;48:953-9.
  5. Iorio A, Guercini F, Pini M. Low-molecular-weight heparin for the Long-Term Treatment of Symptomatic Venous Thromboembolism: meta-analysis of the random- ized comparisons with oral anticoagulants. J Thromb Haemost 2003;1:1906-13.
  6. Hull RD, Liang J, Townshend G. Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review. Am J Med 2011;124:756-65.
  7. Ferretti G, Bria E, Giannarelli D, et al. Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral antico- agulants? Chest 2006;130:1808-16.
  8. Romera-Villegas A, Cairols-Castellote MA, Vila-Coll R, et al. Long-term use of different doses of low-molecular-weight heparin versus vitamin K antagonists in the treatment of venous thromboembolism. Ann Vasc Surg 2010;24:628-39.
  9. van der Heijden JF, Hutten BA, Buller HR, et al. Vitamin K antagonists or low- molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2002;1:CD002001.
  10. Das SK, Cohen AT, Edmondson RA, et al. Low molecular weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomised trial. World J Surg 1996;20:521-7.

    628 Correspondence / American Journal of Emergency Medicine 31 (2013) 621630

    Monreal M, Roncales JF, Ruiz J, et al. Secondary prevention of venous thromboembolism: a role for low molecular weight heparin. Haemostasis 1998;28:236-43.

  11. Beckman JA, Dunn K, Sasahara AA, et al. Enoxaparin monotherapy without Oral anticoagulation to treat acute symptomatic pulmonary embolism. Thromb Haemost 2003;89:953-8.
  12. Kucher N, Quiroz R, McKean S, et al. Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism. Vasc Med 2005;10:251-6.
  13. Erkens PM, Gandara E, Wells PS, et al. Does the Pulmonary Embolism Severity Index accurately identify low-risk patients eligible for outpatient treatment? Thromb Res 2012;129:710-4.
  14. Moores L, Zamarro C, Gomez V, et al, on behalf of the IRYCIS Pulmonary Embolism Study Group. Changes in PESI score predict mortality in intermediate-risk patients with acute PE. Eur Respir J 2012 [Epub ahead of print].
  15. Jaff MR, McMurtry MS, Archer SL, et al. American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123: 1788-830.
  16. Torbicki A, Perrier A, Konstantinides S, et al, Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29: 2276-315.
  17. Koracevic GP. Time to individualize duration of parenteral anticoagulation in pulmonary thromboembolism? Am J Emerg Med 2012;30:1004-6.
  18. Marchetti M, Pistorio A, Barone M, et al. Low molecular weight heparin versus warfarin for secondary prophylaxis of venous thromboembolism: a cost- effectiveness analysis. Am J Med 2001;111:130-9.
  19. Kher A, Samama MM. Primary and secondary prophylaxis of venous thromboembolism with low-molecular-weight heparins: prolonged thrombo- prophylaxis, an alternative to vitamin K antagonists. J Thromb Haemost 2005;3:473-81.

    ST-segment elevation: are we cautious enough??,??

    oxide and thereby aggravates Coronary vasospasm [7]. Thus, a combination of multiple mechanisms might have played a role for the ST elevation.

    Hence, chest pain with ST-segment changes is not always synonymous with acute coronary syndrome, and there is no skepticism that early coronary reperfusion is beneficial in STEMI. Nevertheless, maintaining a high index of clinical suspicion of conditions mimicking STEMI is crucial as the advantages of Timely intervention in patients with STEMI should be weighed against the possible risks caused by thrombolysis and by a delay in the treatment of the underlying diseases that mimics STEMI. Therefore nonCardiac conditions causing STEMI have to be reinforced in regular teaching and training programs and remembered by emergency medical practitioners.

    Subramanian Senthilkumaran MD Department of Emergency & Critical Care Medicine Sri Gokulam hospital & Research institute

    Salem-636004, Tamil Nadu E-mail address: [email protected]

    Ramachandran Meenakshisundaram MD

    Chennai Medical College Hospital & Research Center

    Irungalur, Trichy, India

    Rishya Manikam MD

    University Malaya, Kuala Lumpur, Malaysia

    Ponniah Thirumalaikolundusubramanian MD

    Chennai Medical College Hospital & Research Center

    Irungalur, Trichy, India

    To the Editor,

    We read the case report of Sharma et al [1] with great interest and would like to share some more information. Although myocardial infarction has to be considered as the first and foremost with ST-segment elevation from an electrocardiogram for optimal management, however, there are various noncardiac fatal conditions present as ST-segment changes in electrocardiogram [2]. Furthermore, targets for reperfusion have drastically altered the assessment of patients with chest pain. Gu et al [3] reported an alternative diagnosis in 2.3% of patients with suspected ST-segment elevation myocardial infarction referred for primary percutaneous coronary intervention, although it varies between 1.4% and 13% in literature [4]. We have previously reported a case series of ST-segment abnormalities in Spontaneous pneumothorax along with mechanisms for these changes [5].

    Interestingly, Sampson et al [6] hypothesized that hypoxic vasoconstriction of the pulmonary vessels of the collapsed left lung with resultant diversion of cardiac output to right lung might have increased the pressure in the pulmonary vasculature causing sudden pressure load on right ventricle leading to focal or global myocardial ischemia, which might have triggered epicardial or microvascular coronary vasospasm resulting in ST elevation. Severe hypoxemia induces a catecholamine surge, which increases myocardial workload and results in ischemia. In addition, change in intrapleural pressure influences the venous return and stroke volume. Tachycardia as seen in the patient reported might have increased the oxygen demand and shortened diastolic perfusion, which have led to ischemia of myocardium. Hypoxia also generates super oxide, which abolishes the vasodilatory effect of nitrous

    ? Financial support–Nil.

    ?? Conflict of interest–Nil.

    http://dx.doi.org/10.1016/j.ajem.2012.12.017

    References

    Sharma AK, Heist EK, Ferrell M. Treatment for ST-elevation myocardial infarction– bronchoscopy. Am J Emerg Med 2012;30:1660.e1-4.

  20. Wang K, Asinger RW, Marriott HJ. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med 2003;349:2128-35.
  21. Gu YL, Svilaas T, van der Horst IC, Zijlstra F. Conditions mimicking Acute ST-segment elevation myocardial infarction in patients referred for primary percutaneous coronary intervention. Neth Heart J 2008;16:325-31.
  22. Larson DM, Menssen KM, Johnson RK, Sharkey SW, Burke MN, Harris J, et al. False positive ST elevation in patients undergoing direct percutaneous coronary intervention-Abstract 1756. Circulation 2006;114:II_346.
  23. Senthilkumaran S, Meenakshisundaram R, Michaels AD, Thirumalaikolundusubramanian

    P. Electrocardiographic changes in spontaneous pneumothorax. Int J Cardiol 2011;153: 78-80.

    Sampson M, Rose Jr CE. Reversible ST-segment elevation associated with atelectasis of the left lung. South Med J 2005;98(9):950-2.

  24. Zou MH, Bachschmid M. Hypoxia-reoxygenation triggers coronary vasospasm in isolated bovine coronary arteries via tyrosine nitration of prostacyclin synthase. J Exp Med 1999;190:135-9.

    prehospital thrombolysis expansion may raise the rate of its inappropriate administration in ST-elevation acute myocardial infarction induced by aortic dissection

    To the Editor,

    Acute myocardial infarction (AMI) is major cause of death worldwide. Coronary heart disease alone caused ?1 of every 6 deaths in the United States in 2009 [1]. Each year, an estimated

    ?635000 Americans have a new coronary attack (defined as first

Leave a Reply

Your email address will not be published. Required fields are marked *