Sales of mythical new oral anticoagulant drugs

Thrombosis refers to blood clots or deposits formed by the aggregation of insoluble substances in the blood.
It is the root of the three major cardiovascular diseases, namely heart disease, stroke and venous thromboembolism (VTE)
.
In the United States, 100,000 to 300,000 people die from venous thrombosis each year.
In Europe, 500,000 people die from venous thrombosis each year.
In China, the number of deaths caused by cardiovascular and cerebrovascular diseases accounts for 22.
5% of the total
.
In the process of preventing and treating cardiovascular and cerebrovascular diseases, anticoagulation therapy is the main method
.
PART 01.
Coagulation Cascade Coagulation is the process by which soluble fibrinogen in plasma turns into insoluble fibrin
.
Under normal circumstances, clotting proteins circulate in the blood in an inactive form
.
When the blood vessel is injured, the body will trigger a coagulation cascade reaction, the endogenous coagulation pathway (such as coagulation factor XIIa, Xia, IXa and Villa) and a series of coagulation factors of the exogenous coagulation pathway (such as tissue factor, coagulation factor VIIa) Sequential enzymolysis is activated, and finally through the common coagulation pathway, that is, factor Xa and factor Va form a prothrombin complex with the participation of calcium ions and phospholipid membranes, which convert prothrombin into thrombin (thrombin), and thrombin converts fibrin into fibrin.
The original enzymatically decomposes into fibrin monomers and cross-links to form a stable fibrin clot (fibrin), thereby completing the coagulation process
.
The coagulation cascade is shown in Figure 1
.
PART 02.
The development history of anticoagulant drugs The development history of anticoagulant drugs is shown in Figure 2
.
Vitamin K antagonists and heparin have dominated the anticoagulant market for more than half a century
.
Heparin is the earliest anticoagulant drug.
It can interact with various factors in the coagulation cascade.
The clinically used heparin sodium injection can only be used for short-term prevention of thrombosis (not more than 2 weeks)
.
Although it has a very fast onset, it has a high clinical bleeding rate and can also cause a decrease in the number of platelets (heparin-induced thrombocytopenia, HIT).
About 3% of patients will develop HIT, which further increases the risk of thrombosis
.
Low molecular weight heparins (LMWHs) can significantly reduce the incidence of HIT.
With enoxaparin as a representative, it can not only prevent venous thromboembolism, but can also be used to treat acute coronary syndromes.
In 2008, its sales were as high as US$4 billion
.
However, although LMWHs have high bioavailability and low bleeding rate, they require subcutaneous injection, which reduces the patient's compliance with medication
.
Vitamin K antagonists are represented by warfarin, which can inhibit the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, thereby preventing the continued growth of thrombus
.
Although warfarin has a significant anticoagulant effect, the use of warfarin in patients with atrial fibrillation can reduce the incidence of stroke by 64%, but the drug has a serious and fatal risk of bleeding, and the pharmacokinetic curve is difficult to predict.
There are interactions between these drugs and food, and the International Normalized Ratio (INR) needs to be monitored and the INR value controlled at 2-3 when using it
.
Therefore, the development of anticoagulants with a linear relationship between pharmacokinetics and pharmacodynamics can improve safety, reduce bleeding risks, and improve patient compliance with medication.
These needs provide a broad market prospect for new oral anticoagulants.
And development opportunities
.
It can be clearly seen from Figure 3 that the market share of LMWHs has shrunk from US$4.
5 billion in 2008 to US$2.
85 billion in 2014.
The new oral anticoagulant drugs, such as apixaban, rivaroxaban and darby As represented by galtranxetil, its sales rose rapidly from US$835 million in 2008 to US$5.
3 billion in 2014, and sales increased by as much as 5 times.

.
Figure 3.
The global anticoagulants market (left) from IMS Health, evaluate Pharma and datamonitor; The sales of dabigatran etexilate, rivaroxaban and apixaban in 2015-2020 (right) from Yaodu.
01 dabigatran etexilate) is a reversible direct thrombin inhibitors (DTIs) developed by Boehringer Ingelheim.
It is the first new oral anticoagulant drug to be marketed in 50 years after the emergence of warfarin.
, Approved by EMA in 2008, the trade name is Pradaxa? It is used to treat stroke, pulmonary embolism, venous thrombosis and venous thromboembolism.
Sales in 2019 reached US$1.
712 billion
.
Dabigatran etexilate effectively and selectively inhibits the formation of thrombin in a concentration-dependent manner.
Its blood concentration is related to blood coagulation parameters, such as activated prothrombin time (aPTT) and prothrombin time (prothrombin time).
, PT), thrombin time (TT) and ecarin clotting time (ecarin clotting time) are closely related
.
Therefore, compared with warfarin, the efficacy of dabigatran etexilate is predictable, and there is no need for regular blood coagulation monitoring during clinical use, and the drug is not metabolized by the liver CYP enzyme, and the drug is taken with proton pump inhibitors and H2 receptor antagonists.
There is no drug-drug interaction with amiodarone
.
The RE-LY study is a phase III clinical trial that randomly compared the effectiveness and safety of dabigatran etexilate and warfarin in 18113 patients with atrial fibrillation (with an average follow-up of 2 years)
.
The study evaluated two dosage regimens, 110 mg or 150 mg twice daily
.
With stroke or systemic embolization as the primary efficacy endpoint, the efficacy of dabigatran etexilate at the two doses was not inferior to warfarin, and the efficacy of the 150 mg dose group was superior to warfarin
.
However, the incidence of major bleeding in the 150 mg dabigatran etexilate group was similar to that in the warfarin group, and the 110 mg dabigatran etexilate significantly reduced the incidence of major bleeding
.
02Rivaroxaban Rivaroxaban (rivaroxaban) is a reversible factor Xa inhibitor developed by Bayer.
It was approved for marketing by EMA in 2008, and its trade name is Xarelto? It is used to treat pulmonary embolism, stroke, and coronary.
Arterial disease, peripheral arterial disease, venous thrombosis, venous thromboembolism and atherosclerosis, sales in 2020 will reach 7.
893 billion US dollars
.
The coagulation factor Xa inhibitory activity of rivaroxaban is dose-dependent, which can prolong the time of PT and aPTT.
There is no need to monitor the INR value during clinical use
.
Although rivaroxaban does not induce or inhibit CYP enzymes, it is metabolized by CYP3A4 and CYP2J2, and rivaroxaban is also a P-gp substrate.
Therefore, when using potent inhibitors or inducers of these enzymes, its biological Utilization will be affected
.
The ROCKET study is a phase III clinical trial of rivaroxaban.
The results show that the annual incidence of stroke or systemic embolism after treatment with rivaroxaban (1.
71%) is lower than that of warfarin (2.
16%).
Rivaroxaban is not inferior to warfarin in terms of efficacy endpoints (stroke and non-central nervous system embolism)
.
03 Apixaban Apixaban (apixaban) is a reversible factor Xa inhibitor developed by Bristol-Myers Squibb.
It was approved for marketing by EMA in 2011.
Its trade name is Eliquis? In the treatment of venous thromboembolism, thrombosis and stroke, sales in 2020 will exceed 10 billion U.
S.
dollars (11.
412 billion U.
S.
dollars)
.
Since the blood concentration of apixaban has a good correlation with aPTT and PT values, its anticoagulant effect can be predicted
.
Although apixaban is mainly metabolized by CYP3A3 and CYP1A1/2, the metabolic profile of apixaban appears to be safer than other related compounds in terms of potential drug interactions
.
The ARISTOTLE study is a phase III clinical trial of apixaban.
A total of 18,201 patients with atrial fibrillation were recruited, of which 4808 had a history of moderate or severe valvular disease or a history of valve surgery
.
Among the 13389 patients with avalvular heart disease, 6681 received apixaban and 6708 received warfarin; of the 4808 patients with avalvular heart disease, 2438 received apixaban and 2370 received warfarin.

.
Regardless of the presence or absence of valvular heart disease (VHD), after treatment with apixaban, the incidence of stroke or systemic embolism and the incidence of major bleeding were significantly reduced compared with warfarin
.
PART 03.
Summary With the increase of the aging of the population, the incidence of cardiovascular and cerebrovascular diseases has increased, and the market development momentum of new oral anticoagulants that are safer and more convenient to use has become stronger
.
Although the aforementioned three anticoagulants have predictable pharmacokinetic behavior and do not require regular coagulation monitoring, more detailed comparative studies are still needed to determine whether these new drugs have significant differences in efficacy and safety
.
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et al.
Apixaban in Comparison With Warfarin in Patients with Atrial Fibrillation and Valvular Heart Disease: Findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.
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