Anticoagulation therapy in Iran

Introduction

Thrombosis and bleeding are two sides of the double-edged sword of hemostasis. Bleeding disorders are associated with a high rate of morbidity and mortality (1). Management of thrombosis and bleeding has improved significantly in recent years. Advancements in recombinant coagulation factors synthesis have made a breakthrough in the management of the bleeding disorders and has made significant changes in affected patients’ life quality (2). On the other side, with the advent of new anticoagulants, prophylaxis, and management of thrombotic events, as a leading cause of morbidity and mortality, has both improved significantly (3,4). Vitamin K antagonists (VKAs) and heparin were, in the recent past, the only available drugs for anticoagulation therapy in thromboembolic disorders (5). Warfarin, the most well-known VKAs, is the commonly used anticoagulants for management of thrombosis and related complications (6). Although warfarin is cheap, and widely available, it has a narrow therapeutic window, several side effects, and requires regular and close laboratory monitoring (7). Heparin, including unfractionated heparin (UFH) and low molecular weight heparin (LMWH), is another commonly used anticoagulant worldwide, but regular monitoring and several potentially severe adverse effects, such as hemorrhage and heparin induced thrombocytopenia (HIT), are the main disadvantages of such parenterally administered anticoagulants (8). Direct thrombin inhibitors (DTIs) and factor Xa inhibitors (FXIs), known as direct oral anticoagulants (DOACs), have a growing role in the management of thromboembolic disorders (9). In the present study, we report different aspects of anticoagulation therapy in Iran, including the type of anticoagulants which are prescribed, clinical indications, and available laboratory monitoring tests.

Anticoagulation therapy in Iran

Anticoagulant therapy is a common practice in Iran, mostly prescribed by cardiologists, hematologists, oncologists, internists, anesthesiologists, and gynecologists. All types of anticoagulants, including the VKAs (warfarin), heparin (UFH and LMWH), and DOACs are available in Iran. Although with the advent of new anticoagulants, the overall pattern of anticoagulant therapy has changed toward the use of DOACs, VKAs are still the most commonly used anticoagulants in Iran (Table 1).

The main reasons for high frequency of warfarin prescription in Iran are low cost, easy laboratory monitoring, good clinical experiences, and the wide availability of reversal agents. Prothrombin time/international normalized ratio (PT/INR) is used for warfarin therapy monitoring. In Iran, UFH is prescribed for various conditions such as management or prophylaxis of venous thromboembolism (VTE), atrial fibrillation (AF), and management of patients with disseminated intravascular coagulation (DIC) (Table 2).

Similar to other parts of the world, bleeding is the most common complication of UFH therapy in Iran. Protamine sulfate is used to reverse the anticoagulant effect of UFH. The dose of protamine sulfate is determined based on the administrated dose of UFH. Due to several advantages, including a lower rate of heparin induced thrombocytopenia (HIT) and osteoporosis, and no need for close laboratory monitoring in most patients, LMWH is used more frequently in Iran than UFH (Table 3).

Among LMWHs, including enoxaparin, dalteparin, and tinzaparin, enoxaparin is the most commonly used agent in Iran. One of the main advantage of LMWH compared with UFH and VKAs, is a lower requirement for close laboratory monitoring. When required, the anti-factor Xa assay is routinely used for monitoring of enoxaparin therapy in Iran. Although LMWH therapeutic monitoring by anti-factor Xa assay is not usually necessary, it is recommended for selected patients such as those who require higher doses of the drug, overweight patients, and patients with renal failure. The major complication of enoxaparin therapy is bleeding, and protamine sulfate and fresh frozen plasma (FFP) are used to reverse the anticoagulant effect of the drug.

In recent years, due to more awareness of physicians, the use of DOACs is increasing, but the high cost of these drugs and lack of clinical experiences are the main obstacles to the widespread use of them (Table 4).

Rivaroxaban is the most widely used FXa inhibitor in Iran, while dabigatran is the most commonly used DTI. In fact, dabigatran is the only used DTI in Iran. Apixaban is the second most common FXa inhibitor prescribed in Iran.

Similar to other anticoagulants, bleeding is the most common complication of DOACs in Iran. There is no specific antidotes for DOACs in Iran, and in emergency situations, FFP, prothrombin complex (PCC), and recombinant factor VII are used to reverse their anticoagulant action (Table 1). Hepatic and renal function analysis is performed in regular intervals on Iranian patients under DOACs therapy.

The role of global hemostasis assays for the monitoring of anticoagulation therapy has increased in Iran, and rotational thromboelastometry (ROTEM) is used for monitoring of anticoagulation therapy, particularly in candidate patients for surgery.

Discussion

With the advent of new anticoagulants, management of thromboembolic complications has significantly improved in recent years (9). Therapeutic options for management of thromboembolic disorders are variable in different countries, mostly due to economic issues (10). Like most countries worldwide, in Iran, as a Middle East country, all types of anticoagulants including VKAs, heparin, and DOACs are available for management of the patients with thromboembolic disorders. Although the use of DOACs has an increasing trend in Iran, warfarin is still the most widely used anticoagulant due to low cost, good clinical experiences, easy laboratory monitoring, and availability and the low cost of warfarin reversal agents. Although an increasing trend in use of DOACs has been reported in other countries like Italy, Finland, and Australia, warfarin remains the most popular anticoagulant worldwide. This popularity is not restricted to developing countries, but includes a considerable number of developed countries like USA, Australia, Italy, and Canada (10-15).

Both types of heparin including, UFH and LMWH are prescribed in Iran. The availability, low cost, easy laboratory monitoring, and good clinical experiences are the reasons for the high prescription of these anticoagulants in this country. LMWH is more commonly used than UFH, in Iran. Antidotes are also available for these anticoagulants in Iran. Similar to Iran, enoxaparin is the most widely used LMWH among US hospitals too. In a study on 224 acute-care hospitals in the USA, it was revealed that enoxaparin is prescribed in more than 80% of hospitals, while dalteparin and tinzaparin were used in 17.3% and 1.6% of hospitals, respectively (16). Based on the efficacy and safety of enoxaparin in different populations, it was revealed that enoxaparin has the widest food and drug administration (FDA) approved indication range. Although the use of DOACs has increased in the recent years, their prescription varies between different countries. For example, in England, it varies from 8% to >60% (17). The use of DOACs, notably rivaroxaban is increasing in recent years in Iran. Although rivaroxaban is the most commonly used DOACs in some countries such as Finland and Slovakia, Chania, and some South-American countries, it is the third most common anticoagulant in the world (10,11,15). Apixaban has been reported as the most common DOACs in North-European and Latin American countries, but is the second most common FXa inhibitor prescribed in Iran (10).

Routine use of DOACs, particularly rivaroxaban, can increase the prescription cost of anticoagulation therapy from 20 to 80 times in Iran. In England, the average cost of warfarin therapy per month is £0.83, while this cost is >£50 for DOACs. In addition, costs of specific antidotes of DOACs are extremely high for clinical use. For example, idarucizumab, as a specific antidote of dabigatran, has a cost of >£2,500 per use (18). Another example is andexanet alfa, an antidote of factor Xa inhibitor, which has a short half-life and high cost (>£1,500) (19). The relative cost for warfarin and heparin antidotes is comparably very low. Specific antidotes of DOACs are not available in Iran, and the physicians have to use alternative choices, including PCC and FFP. For factor Xa inhibitors, 4-factor PCC (4F-PCC) and recombinant activated factor VII are available (20). Further studies are required to confirm the best and most cost-effective approach to anticoagulant reversal. The American College of Cardiology Foundation/American Heart Association recommended FFP and packed red blood cells to control the bleeding in patients under DTI therapy (21). Others recommended hemodialysis to control severe bleeding in patients with renal failure under dabigatran therapy (22).

Further studies reveal that the risk of gastrointestinal bleeding is higher in older patients under DOACs therapy (23). DOACs generate greater risk in patients with renal failure. In such cases, most physicians empirically lower the dose of the drug. In a meta-analysis, it was identified that anti-factor Xa inhibitors may increase the risk of myocardial infarction. In another meta-analysis of randomized controlled trials, it was identified that DOACs are better than warfarin in preventing embolic and hemorrhagic stroke, but gastrointestinal bleeding is higher in patients under DOACs therapy (24). Several studies have also shown a decreased rate of malignancies in patients receiving warfarin therapy, which is an apparent advantage in compared to the newer anticoagulants, especially in the older patients. All of these issues emphasis on a more objective assessment of the current trend towards DOACs as the first-choice of anticoagulant therapy (25).

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Emmanuel J. Favaloro) for the series “Anticoagulant and antithrombotic therapy: globally applied according to local geographical selection criteria” published in Annals of Blood. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aob.2019.11.01). The series “Anticoagulant and antithrombotic therapy: globally applied according to local geographical selection criteria” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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