Abstract:
A Danish study of 2 million women of reproductive age tracked the first-time cases of venous thromboembolism. The aim was to link the simultaneous use of hormonal contraception and non-steroidal anti-inflammatory (NSAIDs) painkillers resulting in thrombotic risks. Previous studies had proven that oral contraceptives increase blood coagulability, but this extensive study demonstrated that women on hormonal therapies should be made aware of using NSAIDs sparingly as it increases the risk of acquiring venous thromboembolism by manifolds.
Introduction:
Venous thromboembolism (VTE) includes both deep vein thrombosis and pulmonary embolism which often remain under-diagnosed 2There is less awareness about VTE which can happen to anyone and can result in disability and is life threatening. It is very much preventable and can be treated if diagnosed early. The blood clot in VTE is usually developed in the lower limbs and pelvis but can also develop in upper limbs. The contributing risk factors are- bone fractures, muscle injury, major surgery, sluggish blood flow for a number of reasons (paralysis, confined in bed, sitting for long), heart disease, lung disease, cancer, chemotherapy, use of contraceptive or hormone replacement therapies, family history, etc. 3
Non-aspirin NSAIDs, especially the non-specific NSAIDs and the Cyclooxygenase 2 blockers have been proven to induce thrombotic effects as they inhibit both the vasodilating and anti-thrombotic prostacyclin along with the thrombotic Thromboxane A2.
Studies have reported that women on oral contraceptives, especially oestrogen containing pills have a 3-5-fold higher incidence of VTE than women who are not taking it. 4
The Danish cohort studied first time women users of NSAIDs aged 15-49 years between 1996 and 2017 from Danish national registry who were on hormonal therapy with no previous history of blood clots, cancer, hysterectomy, or fertility treatment. A positive correlation between oral contraceptives and non-aspirin NSAID users in causing higher incidence of VTE was established. 5
Mechanism of action of NSAIDS and Role in Inducing VTE:
NSAIDs are used to block the cyclo-oxygenase (COX) enzyme that uses arachidonic acid to synthesize prostaglandins. The two forms of COX are COX-1 and COX-2 which have similar functions but are derived from different gene expressions. COX-1 is the constitutive form that is present extensively throughout the body and maintains gastric mucosal stability, influences renal blood flow, and aids in blood clotting. COX-1 activates platelets in the endothelium which synthesizes thromboxane A2 (TXA2), this TXA2 aggregates more platelets for clot formation and is a vasoconstrictor- both are thrombotic function. COX-2 is the inducible form of COX expressed during inflammation due to chemical mediators like cytokines, hormones, tumor promoters and is involved in synthesizing prostaglandins that mediate pain and support inflammatory processes. In the endothelium and smooth muscle cells, COX-2 produces prostacyclin’s (PGI2) especially after cell damage and these PGI2 are natural platelet inhibitors and vasodilators. 6, 7
Fig-1: Prostaglandin, Thromboxane A2, Prostacyclin Synthesis from Cyclooxygenase Pathways, NSAIDs’ anti-inflammatory effect from COX-1 & COX-2 inhibition. 8
Low-dose aspirin is cardio-protective as it irreversibly inhibits COX-1 pathway, this inhibits the cascading actions of formation of TxA2, platelet aggregation and blood clot formation. At the same time, it does not hamper COX-2 activity of producing vasodilators PGI2. Both these actions are cardio protective. 9, 10
Nonspecific NSAIDs like diclofenac, ibuprofen and naproxen reversibly inhibit COX-1 and COX-2, thus inhibiting both the formations of thrombotic TxA2 and the synthesis of anti-thrombotic vasodilators prostacyclin and prostaglandin E2. 11
In patients with existing cardiac and renal diseases it is important to balance the role of TxA2 and PGI2. The use of nonspecific NSAIDs hampers this balance which impairs the vasoconstrictor/dilator stability necessary for homeostasis. 12
Selective COX-2 inhibitors inhibit endothelial COX-2 derived prostacyclin but not platelet COX-1 derived TxA2. So, they cannot block blood clot formation and at the same time inhibits vasodilatory action- this potentially increase cardiovascular and stroke risk. Rofecoxib a selective COX-2 inhibitor was banned in the US as it had caused myocardial infarction and strokes. Celecoxib is in use as COX-2 inhibitor. 13
Hypercoagulability of Oestrogen:
Margaret Sanger, a public health nurse is the pioneer who introduced the term “birth control” in 1914 and fought for decades to establish women’s rights on planned pregnancies and making contraceptives legal. 14
The first-generation contraceptive pill Enovid was approved by FDA in 1960. 15
Today, the fourth generation of oral contraceptives are in use. The use of combined oral contraceptives containing both oestrogen and progesterone is common across the world. However, one of the main risks of using oral contraceptives is VTE as the hormones tend to increase blood coagulability. Women of reproductive age using oestrogen containing oral contraceptives are 3-5 times more prone to develop VTE than women not taking it. The third-generation oral contraceptives containing desogestrel, gestodene, or norgestimate poses more risk.
The plasma concentrations of clotting factors II, VII, X, XII, factor VIII, fibrinogen, and thrombin activatable fibrinolysis inhibitor are increased by oestrogen containing oral pills. A slight decrease of factor V concentration was reported, and factor VIII is known to increase at the least magnitude but in comparison factor VII increases at the greatest magnitude.
Data suggests that the third-generation oral contraceptives containing desogestrel imposes far greater risk in increasing the factor VII in contrast to the second-generation contraceptive that contains levonorgestrel.
Oestrogen increases plasma concentration of all these clotting factors by gene transcription. 16
Cohort Study of VTE Risks on Women:
Combined hormonal contraceptives containing both oestrogen and progestin, are a recognized risk factors of VTE for lower limb. The degree of risk is influenced by the dose of estrogen and the type of progestin, with estrogen promoting hypercoagulability by affecting the transcription of genes for various coagulation factors. Progestin’s influence on the coagulation system is complex, with high-dose progestin associated with an increased risk of VTE, while the levonorgestrel-releasing intrauterine device, delivering a small progestin dose, has shown reduced risk.
Additionally, systemic non-aspirin NSAIDs, including traditional ones like ibuprofen and newer COX-2 inhibitors are linked to arterial and venous thrombogenic disease development. Selective COX-2 inhibitors mainly deactivate the inflammatory process but as an additional effect they reduce prostacyclin formation and since they do not inhibit COX-1 pathway TxA2 remains activated to promote platelet aggregation and blood clotting, thus this may lead to formation of venous thrombosis. The widespread use of oral contraceptives in conjunction with NSAIDs globally and its positive effect on venous thromboembolic disease is a public health concern and must be shared widely.
The Danish cohort study used the data from the Civil Registration System, the National Registry of Causes of Death, the National Patient Registry, and the National Registry of Medicinal Product Statistics. Prescriptions information were derived from the National Registry of Medicinal Product Statistics. Use of hormonal contraception was categorized as high-risk hormonal contraceptives, medium risk hormonal contraceptives, and low/no risk hormonal contraceptives. The time exposed to systemic non-aspirin NSAIDs was counted to last one week from the date of the filled prescription. The overlap time using both group of drugs was the time considered to be concomitant use. 17
2.0 million Women aged 15-49 years were included who had no history of thrombotic events, cancer, thrombophilia, or infertility treatment. The exposure was defined as use of hormonal contraception and NSAIDs, categorized into eight groups according to the type and risk of hormonal contraception and the active ingredient of NSAIDs. Ibuprofen was the most frequently used NSAID (60%), followed by diclofenac (20%) and naproxen (6%). The high risk and medium risk hormonal contraception considered in the study were administered orally; the use of the levonorgestrel releasing intrauterine system were accounted for low/no risk hormonal contraceptive. 18
Fig-2: The Study Cohort, with subjects’ numbers, confounders and exceptions. 19
The outcome was studying the first time diagnosis of lower limb deep venous thrombosis or pulmonary embolism, identified from the National Patient Registry and the National Registry of Causes of Death. The outcome was confirmed by imaging or anticoagulation therapy in 81% of cases. The study adjusted for several potential confounders, such as age, calendar time, educational level, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, inflammatory diseases, and use of tranexamic acid. Women who were pregnant, were six months into their post-natal and 12 weeks after other type of pregnancy terminations were left out from the study. 20
The study found that use of NSAIDs was associated with an increased risk of venous thromboembolism, with the magnitude depending on the user status of hormonal contraception. When NSAIDs and oral contraceptives were not used together, the adjusted incidence rate ratio of venous thromboembolism was 8.1 for NSAID alone, 4.2 for high-risk hormonal contraception use, 3.0 for medium risk hormonal contraception use, and 1.1 for low/no risk hormonal contraception use only. The corresponding rate ratios increased to 58%, 23%, and 19% for concomitant use of NSAIDs and high risk, medium risk, and low/no risk hormonal contraception, respectively. 21
Conclusion:
The study concluded that NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age, and the number of extra events was significantly larger with concomitant use of high/medium risk hormonal contraception compared with low/no risk hormonal contraception. It was suggested that women needing both drugs should be advised accordingly.
Authors of this article:
- Dr. Maliha Mannan Ahmed has an MBBS (BMC), MBA (ULAB) and Masters in Healthcare Leadership (Brown University) and is the Executive Editor of The Coronal.
- Dr. Nahian Al Sakib Nitol is a Senior Executive, Strategic Medical Marketing Department, Radiant Pharmaceuticals Limited.
Reference
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