Blood Clot Prevention
You may not know it, but if you are over 50 the greatest threat to your continued existence is the formation of abnormal blood clots in your arteries and veins.
The most common form of heart attack occurs when a blood clot (thrombus) blocks a coronary artery that feeds your heart muscle. The leading cause of stroke occurs when a blood clot occludes, or obstructs, an artery supplying blood to your brain. Formation of vascular blood clots is also a leading cause of death in cancer patients because cancer cells create conditions that favor clotting.
While normal blood clots are a natural part of healing, abnormal arterial and venous blood clots are a significant cause of death and disability (Mannucci 2011).
The good news is that health-conscious individuals already take a wide variety of nutrients through their diet and supplement program that drastically reduce their risk of developing thrombosis, which is the medical term for an abnormal vascular blood clot.
Certain individuals, however, have underlying medical conditions that predispose them to developing thrombotic events. These include atherosclerosis, mechanical heart valves, atrial fibrillation, venostasis, blood clotting disorders, and cancer. These individuals must take special precautions to protect against thrombosis.
Conventional medicine offers drugs proven to reduce thrombotic risk via specific mechanisms. These drugs fail, however, to neutralize the broad array of mechanisms that can induce a thrombotic event, which is why a comprehensive thrombosis prevention program is so critically important to those at high risk.
This protocol first discusses some technical details about thrombosis, the conventional drugs that doctors prescribe, and important blood tests to consider. It then reveals little-known methods of inhibiting a multitude of thrombotic risk factors that mainstream doctors overlook.
Life Extension believes patients succumb to thrombotic events, even when taking powerful anti-coagulation drugs such as warfarin, because their doctors failed to suppress the many other underlying risk factors that cause abnormal clots to form inside a blood vessel.
The Flaws of Mainstream Therapies
The most effective means of blood clot management is prevention. For high-risk patients, mainstream prophylaxis against thrombosis and its complications often includes powerful anti-clotting medications. These require careful monitoring and inconvenient dietary restrictions.
Conventional medications used to prevent blood clots, such as warfarin (Coumadin®), increase the potential for serious bleeding as well as the risk of mortality from traumatic injuries (Dossett 2011). Moreover, warfarin may lead to significant long-term side effects, such as increased risk of atherosclerosis and osteoporosis.
Life Extension has identified a strategy to reduce the detriments of long-term warfarin therapy. Judicious use of vitamin K2 has been shown in peer-reviewed studies to reduce the fluctuation in coagulation status associated with warfarin therapy. This notion runs contrary to that of conventional medicine, whose best advice is to totally eliminate vitamin K from the diet during warfarin therapy, an outdated guideline that compromises vascular and skeletal health.
Next-generation anticoagulant medications that overcome these vascular and skeletal risks are emerging, yet they still lack sufficient data from clinical trials to solidify them as first-line treatments. The most promising of these new drugs is dabigatran (Pradaxa®); however, early trials indicate that dabigatran may be more effective for reducing stroke risk in patients with atrial fibrillation (Peetz 2010; Houston 2009).
Life Extension emphasizes that optimal thrombosis risk reduction can never be viewed in isolation, but must encompass a global strategy. Measures to reduce the risk of blood clots include reducing chronic inflammation, maintaining healthy body weight, reducing cholesterol, suppressing homocysteine levels, and lowering blood pressure. Additionally, the use of scientifically studied nutrients to target abnormal platelet aggregation can intervene in the thrombotic process before it causes a life-threatening medical emergency.
What is a Blood Clot?
A normal blood clot consists of a "clump" of blood-born particles that have become "stuck" together inside a blood vessel; this usually occurs at the site of a blood vessel injury and is part of the normal healing process. However, clotting also can occur in areas where blood flow is slow or stagnant, such as in a blood vessel occluded, or obstructed, by atherosclerotic plaque. A blood clot that develops in a blood vessel or the heart and remains there is called a thrombus, while a blood clot that has broken loose and floats freely through the circulatory system is called an embolus.
Blood clots are made up of:
Platelets: Small fragments of larger cells called megakaryocytes, platelets circulate through the blood and carry important substances such as proteins and other cellular signaling molecules. A platelet has a lifespan of about 7–10 days.
Red Blood Cells: The most common type of blood cell, red blood cells transport oxygen from the lungs and distribute it to all the tissues of the body.
White Blood Cells: The cells of the immune system, white blood cells originate in the bone marrow as stem cells that differentiate into various types of immune cells.
Fibrin: A web-like proteinaceous gel, fibrin binds the other components of the clot together.
A clot formation can be especially dangerous if it blocks blood flow to organs or tissues. For example, blockage of the coronary arteries (the blood vessels that directly supply oxygen to the heart muscle itself) can result in myocardial infarction (a heart attack), and death of heart muscle tissue.
An unstable thrombus can break away from the vessel wall and cascade freely through the bloodstream. This thrombus can become problematic if it becomes wedged in a blood vessel too small to allow its passage, obstructing blood flow and impairing oxygen delivery to tissue. This blockage is called an embolism. Cerebral embolism is one such example—an embolism in the small arteries of the brain can cause an embolic stroke.
Arterial thrombosis is associated with several life-threatening complications (Table 1). Clots in the veins (venous thrombosis) of the legs are relatively common, and pose a significant risk of forming emboli that can travel to the lungs, causing a potentially fatal pulmonary embolism.
Risk Factors for Thrombosis
The risk factors for thrombosis are believed to increase clotting through one or more of these three mechanisms: 1) altering or damaging the blood vessel lining (endothelium); 2) impairing or slowing the flow of blood; or 3) promoting a state that favors excess coagulation (hypercoagulation).
Alteration of the blood vessel lining (endothelium) produces areas of disturbance that are not necessarily tears, but may nonetheless mimic the physiology of vascular injury, thus encouraging the recruitment of platelets and the clotting process. Factors that pose a risk to endothelial cell health include:
- Abnormal blood lipids, particularly elevated total cholesterol, LDL (low-density lipoprotein) cholesterol, triglycerides, and low HDL (high-density lipoprotein) cholesterol. Blood lipid values outside of optimal ranges (see Table 2, below), are one of the risk factors for atherosclerosis, which causes arterial plaques on blood vessel walls. Clots can form on or near the lipid-rich arterial plaques in vessel walls, disrupting blood flow and increasing heart attack or stroke risk. Scientific strategies for cholesterol risk reduction are available in Life Extension's Cholesterol Management protocol.
- Elevated high-sensitivity C-reactive protein (hsCRP). hsCRP is an indicator of inflammation and blood vessel injury; high levels are predictive of future risk of heart attack or stroke (Ridker 2008). CRP also exerts several pro-thrombotic activities, and may be associated with risk of venous thrombosis (Lippi 2010).
- Hypertension. Sustained high blood pressure compromises the integrity of the endothelium, and can cause endothelial activation and initiation of clotting (Schmieder 2010). For optimal endothelial protection and blood clot prevention, a target blood pressure of 115/75 mmHg is suggested. Those with blood pressure higher than the optimal range are encouraged to read Life Extension's Blood Pressure Management protocol.
- Elevated glucose. Elevated blood glucose levels, even those that remain in the lab-normal range, may significantly increase the risk of developing a blood clot. In fact, a clinical study involving patients with coronary artery disease (CAD), found that patients with fasting glucose levels above 88 mg/dl had greater platelet dependent thrombosis than those with levels below 88 mg/dl. The authors of this study remarked: "The relationship is evident even in the range of blood glucose levels considered normal, indicating that the risk associated with blood glucose may be continuous and graded. These findings suggest that the increased CAD risk associated with elevated blood glucose may be, in part, related to enhanced platelet-mediated thrombogenesis" (Shechter 2000).
Life Extension suggests fasting glucose levels be kept between 70–85 mg/dL to limit glucose-induced platelet aggregation and to promote optimal overall health.
- Excess abdominal body fat. Abdominal obesity, also known as android obesity, consists of excessive deposition of fat tissue around the trunk of the body (e.g. the belly). The fatty tissue around the trunk is prone to secrete inflammatory chemicals and cause high blood sugar and hypertension, all factors that pose dire risk to the health of the endothelial cells. Maintaining an ideal body weight is critical to reducing thrombosis risk.
- Elevated homocysteine has been associated with a 60% increase in venous thrombosis risk for each 5 µmol/L increase in concentration (den Heijer 2005). Homocysteine damages the endothelium, increases endothelial cell and platelet activation, and lowers fibrinolytic (clot breakdown) activity (Di Minno 2010). Life Extension recommends keeping homocysteine levels below 7-8 µmol/L for optimal health (Table 2); guidelines for doing so are discussed in the Homocysteine Reduction protocol.
- History of stroke, transient ischemic attack, heart attack, or coronary artery disease all indicate a susceptibility to arterial thrombosis and are among the strongest predictors of future thrombotic events.
*Note: In addition to these factors listed above, additional discussion of risk factors that compromise endothelial health (and therefore increase risk for thrombosis) can be found in the Life Extension Magazine article entitled "How to Circumvent 17 Independent Heart Attack Risk Factors".
Interrupted blood flow stimulates thrombosis by allowing the localized accumulation of circulating platelets and clotting factors and by increasing the probability of clotting reactions. Risk factors include:
- Sedentary behavior, either as inactive lifestyle, or due to extended immobilization such as during hospitalization or long-distance travel (Lippi 2009). According to the CDC, adults aged 18+ should engage in at least 2.5 hours of moderate intensity aerobic exercise each week, and full-body strength training at least twice a week. Even greater health benefits are available through 5 hours of moderate-intensity aerobic exercise each week combined with full-body strength training two or more days a week.
- Surgeries of the lower extremities (hip, knee, ankle) increase thrombosis risk either due to trauma to the veins during surgical manipulation, or immobilization during recovery (Stamatakis 1977). Without treatment, the incidence of deep vein thrombosis following total hip or total knee replacement surgery is as high as 40–60% (Baser 2011).
- Atrial fibrillation, the most common type of abnormal heart rhythm, can lead to blood pooling in the heart and subsequent clot formation in the left atrium, increasing stroke risk 5-fold (Xue 2010).
Hypercoagulable states (sometimes called thrombophilias) are conditions in which the nature or composition of the blood encourages coagulation. Some hypercoagulable states are inherited disorders that increase the activity of clotting factors or reduce the activity of natural anticoagulants. Some of the more common non-genetic hypercoagulable states include:
- Thyroid disorders, which alter the balance of clotting factors and anticoagulants and can increase the risk of thrombosis. Hyperthyroidism (high thyroid function) increases the risk of thrombosis due to disruption of the clotting process, such as increased production of clotting factors, increased thrombin activity, and reduced rate of fibrinolysis (clot breakdown) (Erem 2011). Hyperthyroidism also can increase blood volume, which can lead to high blood pressure and cardiac arrhythmias, both of which are risk factors for thrombosis (Franchini 2006). In hyperthyroid patients, the incidence of arterial thrombosis, especially cerebral thrombosis, is between 8 and 10% (Burggraaf 2001). Hypothyroidism (low thyroid function) also increases the risk of thrombosis. Hypothyroid patients cannot clear clotting factors from the blood as quickly, have elevated levels of fibrinogen, and have reduced rates of fibrinolysis (Erem 2003).
- Elevated plasma fibrinogen, the main coagulation protein, which may result from a variety of conditions such as smoking, thyroid disorders, or infection (Folsom 1995). A comprehensive review of observational studies estimated that a 98 mg/dL reduction in fibrinogen concentration would lead to a relative risk reduction of 80% in coronary heart disease (Folsom 1995).
- Pregnancy, which shifts the balance of hemostatic factors towards coagulation and enhances the activation of platelets, especially in pre-eclampsia (preganacy-associated hypertension), which may affect 2–4% of pregnancies (de Maat 2011).
- Cancer, which can increase risk of venous thrombosis 4- to 7-fold, especially in metastatic cancers or those where the infiltration of tumors or compression of blood vessels disrupt blood flow (Streiff 2011). Pancreatic, brain, and gastric cancers especially increase the risk of thrombosis (Streiff 2011).
Blood clots may be predictive of cancer risk as well. In a case-control study involving nearly 60,000 patients, the likelihood of developing any cancer within 6 months of diagnosis of venous thromboembolism (VTE) was 420% higher than that of the general population (Murchison 2004). Particularly, cancer of the ovary was more than 700% more likely, while non-Hodgkins lymphoma and Hodgkins disease were 500–600% more likely within a year of VTE.
Tumors exert a number of pro-thrombotic effects on the blood, as does chemotherapy itself (Kirwan 2003). Unfortunately, once cancer has progressed sufficiently to cause a blood clot, it is usually in an advanced stage, and the survival rate of patients diagnosed with cancer within one year of VTE is poor (Sorensen 2000).
Alarmingly, the close link between cancer and thrombogenesis appears to be underappreciated by conventional physicians. A small survey of oncologists revealed that 27% believed cancer patients were not at increased risk for clotting (Kirwan 2003). Similarly, another survey found that the majority of oncologists utilize thromboprophylaxis in cancer patients very rarely, despite the fact that VTE is a leading cause of death in this population (Kakkar 2003).
Additional risk factors include age, female sex, smoking, and obesity; additionally, surgery can increase thrombosis risk.
Blood Clotting Mechanisms
Hemostasis, a process that maintains the blood in a free-flowing state and helps stop bleeding during injury, is critical for survival. Blood clotting or coagulation is necessary to repair not only large injuries to blood vessels, but also the thousands of microscopic internal tears that happen daily under normal circumstances. Without a proper hemostatic response, the smallest of vessel injuries would lead to fatal hemorrhage (bleeding).
However, if the intricate balance among hemostatic mechanisms is disturbed, the tendency for a clot to become pathologic dramatically increases. The steps below briefly outline key aspects of the clotting process. This list also highlights points at which some drugs and natural compounds can combat derangement of the clotting system and offset thrombosis risk.
Normal blood clotting is a complex process, consisting of three major phases: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a clot that seals the hole until tissue repair occurs.
The following four steps summarize clot formation, and also highlight key areas that pharmaceutical drugs and some natural compounds target in order to impede clotting:
- Vasoconstriction: Endothelial damage occurs, leading to neurogenic vessel constriction and decreased blood flow near the site of injury. This creates a local environment that favors clotting. Examples of injuries that may initiate the clotting process include rupture of an atherosclerotic plaque, or homocysteine-induced endothelial damage.
- Damage to the endothelium liberates sub-endothelial collagen and tissue factor (factor III), which initiate the intrinsic and extrinsic clotting pathways, respectively, in the immediate area (details in "secondary hemostasis" below).
- Intervention: Polyphenolic antioxidants, such as punicalagins from pomegranate, oligomeric procyanidins from grape seed, and trans-resveratrol, protect endothelial cells against injury and help maintain flexibility of blood vessels.
- Platelet adhesion and activation
- As circulating platelets pass by the site of vessel wall injury, receptors on their surfaces bind to exposed collagen and membrane proteins on activated endothelial cells, causing adhesion of platelets at and around the site of injury. This adhesion is mediated by von Willebrand factor and P-selectin.
- Intervention: Curcumin, a bioactive compound derived from the spice turmeric, acts to suppress P-selectin expression and limits platelet adhesion by this mechanism (Vachharajani 2010).
- Binding of the surface receptors leads to several molecular events that "activate" the platelets, causing release of adenosine diphosphate (ADP) from secretory granules within the platelet.
- Intervention: Bioactive compounds in garlic work to suppress platelet granule release (Mousa 2010).
- ADP binds to surface receptors called P2Y1 and P2Y12 on nearby platelets. This binding causes increased synthesis of thromboxane A2 (TXA2) via conversion of the inflammatory omega-6 fatty acid arachidonic acid by the enzyme cyclooxygenase-1 (COX-1).
- Intervention: Aspirin inhibits the activity of COX-1 for the entire lifespan of the platelet, which is about 7–10 days.
- Intervention: The omega-3 fatty acids EPA and DHA from fish oil counteract the synthesis TXA2 by competing with omega-6 fatty acids as substrates for the COX enzyme (Tapiero 2002).
- Binding of P2Y1 and P2Y12 by ADP also causes the expression of another surface receptor, called glycoprotein IIb/IIIa (GPIIb/IIIa). The significance of GPIIb/IIIa will be examined in the "platelet aggregation" section below.
- Intervention: The "blood thinning" drugs Plavix® (clopidogrel) and Ticlid® (ticlopidine) block ADP from binding to the P2Y12 receptor for the entire lifespan of the platelet, which is about 7–10 days. The drug Effient® (prasugrel) is a reversible inhibitor of P2Y12; its effects last about 5–9 days.
- Additional factors, including newly synthesized thromboxane A2, increases expression of the surface receptor GPIIb/IIIa as well.
- This process of platelet activation is self-propagating among platelets that happen to be near each other, and near the site of blood vessel wall injury.
- Platelet aggregation
- Following the activation of platelets as described above, the expressed GPIIb/IIIa surface receptors bind a circulating protein called fibrinogen, which comprises about 4% of total blood protein.
- Intervention: The B-vitamin niacin, which is well known for being heart-healthy, exerts some of its cardioprotective actions by lowering plasma fibrinogen levels, thus attenuating the proclivity for platelets to aggregate and form a clot (Philipp 1998; Johansson 1997).
- Intervention: Vitamin C also appears to lower plasma fibrinogen levels, as suggested by some clinical trials and epidemiological studies (Khaw 1995; Wannamethee 2006).
- Fibrinogen can bind GPIIb/IIIa receptors on adjacent platelets, linking them together in a process known as platelet aggregation.
- Intervention: Tomato bioactives inhibit the function of GPIIb/IIIa, thereby blocking platelets from 1) binding circulating fibrinogen, and 2) binding to each other (O'kennedy 2006).
- In a matter of seconds after vessel wall damage, platelet adhesion, activation, and aggregation culminate in the formation of a platelet plug, temporarily sealing off the injury.
- Coagulation: Simultaneously to the formation of the platelet plug, tissue factor and collagen that were liberated upon vessel wall injury initiate two separate but related coagulation pathways.
- Collagen interacts with factor XII to initiate the intrinsic coagulation cascade.
- Concurrently, tissue factor interacts with factor VII to initiate the extrinsic coagulation cascade.
- Both the intrinsic and extrinsic pathways converge into the common pathway, which, through a complex series of interactions, converts prothrombin (factor II) into an enzyme called thrombin. This process is locally self-propagating via a process known as amplification, in which thrombin feeds back into the intrinsic pathway to drive further conversion of prothrombin.
- Thrombin then acts upon circulating fibrinogen to convert it into fibrin.
- Intervention: Heparin is a naturally occurring anticoagulant that enhances the action of antithrombin, a glycoprotein that suppresses the ability of thrombin to convert fibrinogen to fibrin, thus slowing the coagulation process. Heparin is helpful when administered during medical emergencies involving atrial fibrillation and deep-vein thrombosis (DVT).
Rarely, some individuals develop a condition called heparin-induced thrombycytopenia (HIT) after receiving heparin. This is due to genetic differences in the immune response of these patients. Patients who develop HIT can be treated more safely with a new heparin alternative called fondaparinux.
- Intervention: Dabigatran (Pradaxa®) is a direct thrombin inhibitor. Dabigatran directly inhibits the action of thrombin, preventing it from converting fibrinogen to fibrin.
- Individual fibrin particles associate with one another to form polymers, which themselves associate into a web-like gel that traps circulating white blood cells, red blood cells, and additional platelets.
- The widely used anticoagulant drug warfarin (Coumadin®) interferes in several steps along both the intrinsic and extrinsic coagulation pathways by inhibiting the activity of vitamin K.
- Vitamin K is required for activation of a number of factors (II, VII, IX, X, protein C, and protein S) involved in coagulation. Vitamin K facilitates carboxylation reactions required to activate these coagulation factors. After vitamin K successfully "carboxylates" a coagulation factor, it transitions to a less active form. In order for vitamin K to carboxylate additional coagulation factors, it must be recycled into its active form; this is accomplished by an enzyme called vitamin K epoxide reductase. Warfarin inhibits vitamin K epoxide reductase and impairs the recycling of vitamin K, thus slowing activation of factors required for coagulation.
- The fibrin gel and included blood cells and platelets then fuse with the platelet plug to reinforce the injury and completely seal it off until tissue repair can begin.
After clotting and coagulation is complete (usually between 3–6 minutes after injury), the trapped platelets within the clot begin to retract. This causes the clot to shrink, and pulls the edges of the injury closer together, squeezing out any excess clotting factors. Then the process of vessel repair can begin. Once healing is complete, the unneeded clot is dissolved and removed by a process called fibrinolysis.
Fibrinolysis involves the cleavage ("cutting") of the fibrin mesh by the enzyme plasmin to release the trapped blood cells and platelets, allowing the clot to "dissolve."
- An enzyme called tissue plasminogen activator (TPA) converts the inactive protein plasminogen into the active plasmin, which then cleaves the fibrin web.
- Intervention: In some medical emergencies involving an embolic event, such as embolic stroke, pulmonary embolism, and myocardial infarction (heart attack), TPA can be administered intravenously to dissolve the blood clot and improve clinical outcome. TPA should be administered as soon as possible after an embolic event for maximum benefit.
- Intervention: Nattokinase, a fermentation product from soy, is an enzyme that has been shown to increase the fibrinolytic activity of plasma in laboratory studies (Fujita 1995).
Conventional Therapies for Blood Clots and Thrombosis Risk Reduction
Two classes of pharmaceutical drugs reduce the risk of thrombosis and its complications, antiplatelet drugs and anticoagulants. Reserved for emergency situations, a third class called thrombolytics/ fibrinolytics break up blood clots and limit tissue damage; tissue plasminogen activator (Activase®) and urokinase (Abbokinase) are two examples.
Antiplatelet drugs inhibit platelet activation and aggregation, an early step in the clotting process. Several classes of antiplatelet drugs inhibit platelet aggregation and activation at a different point in platelet metabolism.
The most common antiplatelet drug is aspirin. It inhibits the enzyme cyclooxygenase (COX), which is responsible for synthesizing thromboxane A2 (Hall 2011). Thromboxane A2 is a factor secreted by platelets to recruit other platelets to the site of injury during the initial stages of the clotting process. The cyclooxygenase inhibitory effect of aspirin is permanent for the life of the platelet (about 7–10 days). Aspirin has been shown effective in preventing complications of several disorders, including hypertension, heart attack, and stroke (Patrono 2008). Importantly, ibuprofen can attenuate the COX inhibitory action of aspirin in platelets; therefore, if low-dose aspirin is being taken preventatively, ibuprofen for pain relief should be taken at least 8 hours apart from aspirin to ensure maximum effectiveness.
Interestingly, aspirin also inhibits the COX enzyme in endothelial cells, but does not exert an irreversible action here. Unlike platelets, endothelial cells contain DNA and RNA and can therefore synthesize new COX enzymes even after aspirin has bound to existing COX enzymes. This dichotomy of aspirin action in platelets versus endothelial cells is significant because the COX enzyme is critical for the synthesis of the anti-platelet, vasodilatory compound prostacyclin (PGI2). Healthy endothelial cells secrete prostacyclin to counteract the action of TXA2 and ensure that a clot does not continue to grow and occlude the blood vessel.
The difference between endothelial cell biology and platelet biology also explains why low-dose aspirin is cardioprotective. Low-dose aspirin does not impair endothelial secretion of prostacyclin because these cells quickly synthesize new COX enzymes and overwhelm low concentrations of aspirin. However, platelets do not synthesize new COX so that aspirin, even in low concentrations, suppresses platelet-derived TXA2 until new platelets arise from the bone marrow. Thus, low-dose aspirin is effective for reducing the risk of pathologic clot formation while maintaining optimal endothelial function.
Aspirin's inhibition of COX also helps explain its potential in cancer reduction as observed in several studies (Rothwell 2011; Rothwell 2010; Salinas 2010; Flossmann 2007). Several types of cancers (particularly breast, prostate, and colon) overproduce the pro-inflammatory enzyme COX-2, which appears to play a role in increasing the proliferation of mutated cells, tumor formation, tumor invasion, and metastasis (reviewed in Cerella 2010; Sobolewski 2010). COX-2 may also contribute to drug resistance in some cancers, and its expression in cancer has been correlated with a poor prognosis (Sobolewski 2010).
A second group of commonly prescribed antiplatelet drugs, including clopidogrel (Plavix™), prasugrel (Effient™), and ticagrelor (Brilinta™), are characterized by their ability to bind to the surface of platelets and block the P2Y12 ADP receptor, inhibiting the platelet from becoming activated. Clopidogrel, the most widely prescribed antiplatelet, is more effective than aspirin in its ability to reduce the aggregation of platelets (CAPRIE Steering Committee 1996). Clopidogrel activity can be enhanced when combined with aspirin (Becker 2008), and this combination has been tested for its efficacy, safety, and cost effectiveness for a variety of clinical applications. In some cases, the combination represents a significant improvement over clopidogrel alone.
In patients with acute coronary syndrome, the CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events) demonstrated that combining clopidogrel and aspirin resulted in a 20% reduction in risk of cardiovascular death, heart attack, or stroke, as compared to aspirin alone after a one year follow up. However, those in the clopidogrel group had an increased risk of bleeding (Yusuf 2001). Similar results were also observed in the COMMIT trial (Clopidogrel and Metoprolol in Myocardial Infarction Trial), in which short-term combination therapy (4 weeks) lowered risk of heart attack, stroke, and death in patients with a previous heart attack (9% risk reduction) (Chen 2005). In both trials the benefits of the combination therapy outweighed the moderate cost increase in treatment. However, for other applications, such as prevention of heart attack in high-risk individuals without established cardiovascular disease, or in the treatment of stable coronary artery disease, treatment with aspirin alone has proven safer and more cost effective than combination therapy (Bhatt 2006; Arnold 2011).
Other clinically important oral antiplatelets include dipyridamole (Persatine™) and cilostazol (Pletal™), which are platelet phosphodiesterase inhibitors. These drugs are used less frequently as large-scale clinical trials have not proved them to be more effective than aspirin and Plavix®.
Anticoagulants inhibit the transformation of fibrinogen into fibrin, one of the last steps in the clotting process that stabilizes a thrombus.
Warfarin has a lengthy list of interactions that can increase the risk of bleeding (hemorrhage). More than 205 pharmaceutical, nutritional, and herbal medicine interactions have been identified for warfarin. Some medications that can potentially interact with warfarin include aspirin, cimetidine, lovastatin, thyroid hormones, and oral contraceptives. Foods and nutritional ingredients such as onions, garlic, ginger, CoQ10, fatty fish, and vitamin E have been reported to increase the risk of bleeding when combined with warfarin; however, many of these reports are anecdotal and may not represent significant concerns (Ulbricht 2008; Shalansky 2007). Many nutritional ingredients that "thin the blood" do so by different mechanisms than warfarin. For instance, rather than interfering with coagulation they may inhibit platelet aggregation, a different step in blood clot formation.
While it is prudent to follow a conservative approach regarding warfarin's potential for interaction with a variety of pharmaceutical and nutritional agents, being overly cautious may cause potential cardiovascular health benefits to go unrealized.
In fact, warfarin combined with conventional antiplatelet drugs has been studied already in patients at high-risk for thrombosis (Vedovati 2010). Additional evidence suggests warfarin can be combined safely with antiplatelet nutrients, such as garlic (Macan 2006), as long as one takes these nutrients responsibly. The most important considerations for individuals who wish to take this approach are monitoring and awareness; patients must work closely with their healthcare practitioner and undergo regular blood testing to measure coagulant activity (see "Testing Clotting Function" below).
Two other oral anticoagulants have been approved recently in the US for use under very specific circumstances: rivaroxaban (Xarelto™), an inhibitor of the clotting factor Xa as a prophylaxis against clotting after orthopedic surgery; and dabigatran (Pradaxa™), an inhibitor of thrombin, for stroke prevention in patients with atrial fibrillation (Mannucci 2011).
Both of these newer therapies may have significant benefits over warfarin and related anticoagulants that interfere with vitamin K metabolism. First, they both inhibit clotting factors that do not depend on vitamin K, so they are less sensitive to dietary fluctuations of vitamin K intake. In trials, neither dabigatran nor rivaroxaban exhibited major interactions with other foods or medications (Steffel 2011). Unlike warfarin, these medications do not need regular blood test monitoring of coagulant status or repeat dosage adjustment (Thethi 2011). In clinical trials, both treatments were at least as effective as warfarin for reducing stroke risk in patients with atrial fibrillation, and preventing/treating deep vein thrombosis, with a reduced risk of bleeding (Connolly 2009; Schulman 2009; Eriksson 2008).
Of these two drugs, dabigatran appears more promising.
For example, in a major hard endpoint study of Pradaxa® (dabigatran) versus warfarin (the RE-LY trial), Pradaxa® was superior for anti-coagulant efficacy at 150 mg 2 times a day with similar major bleeding risk as warfarin treatment (when patients maintained their INR 2.0 to 3.0).
The INR (international normalization ratio) is a test that evaluates the clotting tendency of blood. A normal INR reading is 0.8–1.2, but in patients predisposed to abnormal vascular blood clotting (such as those with mechanical heart valves or atrial fibrillation), physicians seek to boost INR to 2.0–3.0, which reduces clotting propensity. Increasing INR to this higher level (2.0–3.0) also increases bleeding risk. When Pradaxa® was used at a lower dose of 110 mg 2 times daily, it showed similar efficacy to warfarin but with reduced major bleeding risk.
The advantages of Pradaxa® vs. warfarin include:
- Rapid onset of action
- Predictable, consistent anticoagulant effects
- Low potential for drug-drug interaction
- No requirement for anticoagulant blood test monitoring
- Preliminary efficacy and safety advantages vs. warfarin based on initial head-to-head, hard-endpoint data
Disadvantages of Pradaxa® vs. warfarin include:
- No antidote for reversal of over anti-coagulation effect. When too much warfarin is given and the patient's INR indicates they are at risk for a major bleed (or are pathologically bleeding), vitamin K can be injected to immediately reverse warfarin's anti-coagulant effect. If too much Pradaxa® is taken, there is no immediate antidote.
- No long-term safety data on Pradaxa® (the case with virtually all newly approved drugs)
- More expensive than warfarin
Overall, preliminary results suggest benefit (vs. warfarin), but larger/ longer studies must be conducted before definitive conclusions can be drawn. Some data hints that dabigatran may work best in combination with aspirin due to paradoxical platelet-activating effects associated with dabigatran (Houston 2009). A recent comprehensive review of pooled data from seven clinical trials involving over 30,000 subjects found that dabigatran users were statistically 33% more likely to suffer a heart attack or acute coronary syndrome than users of warfarin, enoxaparin (Lovenox®), or placebo (Uchino 2012). The investigators concluded that "The overall benefit and risk balance of dabigatran use appears to be favorable in patients with [atrial fibrillation] because of reduction in ischemic stroke. However, the cardiac risk of dabigatran should be investigated further, especially if it is used in populations at high risk of [heart attack] or [acute coronary syndrome]."
Heparin is a natural anticoagulant that stimulates the activity of antithrombin III and prevents the assembly of fibrinogen molecules into fibrin. Several heparin derivatives, including low-molecular-weight heparin, unfractionated heparin, and fondaparinux (a synthetic heparin derivative) are also clinically important. Heparin and its derivatives are given by injection (Mannucci 2011).
Other potential therapies currently being investigated make use of thrombolytic (clot-dissolving) agents. These include: the co-administration of a clot-dissolving thrombolytic drug and an anticoagulant (warfarin) for deep vein thrombosis treatment; directly infusing the thrombolytic drug tissue plasminogen activator (tPA) into clots in the brain (through a minimally invasive surgical technique) or clots in the leg (by injection) (Johnson 2011; Chang 2011); and the administration of red blood cells coated with tPA to patients, which increases the lifetime of the drug and reduces the likelihood that it will cause excess bleeding (Murciano 2003).