~Thrombosis Prevention, Part 2 - Conventional Treatment
CONVENTIONAL PREVENTION AND TREATMENT
Preventing thrombosis is essential. Inside a healthy circulatory system, the body constantly prevents clotting. Coagulation/anticoagulation is a "mechanism" that the body must maintain in perfect balance. If this process fails, our lives can be in danger in a matter of minutes.
To function optimally, the body must keep blood flowing well in all vessels, regardless of size. When a leak (or damage) occurs in an artery or vein, the body must encourage the coagulation aspect of this balance to seal the leak. However, when there is a significant disturbance or a clot in the blood flow, the consequences are often lethal.
Because so many factors can contribute to coagulation and therefore should be considered for prevention, it is difficult for conventional medicine to control them all. Mainstream medicine can exert control on some crucial steps in the coagulation cascade, but it may often fail to influence them all.
Several prescription drugs address different parts of the coagulation/anticoagulation system:
- Platelet Aggregation Inhibitors
- Other Conventional Platelet Aggregation Inhibition Drugs
- Combining Coumadin with Antiplatelet Agents
- Laboratory Tests for Patient Response to Anticoagulants
* Coumadin (warfarin) inhibits the synthesis of vitamin K-dependent coagulation factors such as Factors II, VII, IX and X and anticoagulant proteins C and S.
* Aspirin inhibits platelet aggregation by interfering with thromboxane synthesis.
* Ticlopidine (Ticlid) inhibits platelet aggregation by interfering with the binding of fibrinogen to the platelet membrane. Ticlopidine is a prescription drug that may be of particular value as an alternative to aspirin. Ticlopidine is often considered in patients that have a high risk of thrombotic stroke and are intolerant to aspirin.
* Heparin (administered intravenously) increases the activity of antithrombin III, which prevents the conversion of fibrinogen to fibrin. Heparin is not absorbed by the gastrointestinal (GI) tract and must be administered intravenously. It is usually only used in emergency situations (e.g., after a stroke).
* Tissue plasminogen factor (t-PA) activates plasmin which breaks apart fibrin. t-PA is used in emergency situations to dissolve blood clots. Streptokinase is another tissue plasminogen factor drug. Both of these drugs are administered intravenously in emergency thrombotic situations (e.g., ischemic stroke or MI).
Platelet Aggregation Inhibitors (Platelet Anti-Aggregation Drugs)
More than any other medication, aspirin is used alone for the prevention of recurrent strokes and transient ischemic attacks (TIAs). Aspirin acts to inhibit blood clotting by reducing platelet aggregation (clumping), thereby preventing the formation of platelet plugs. Aspirin inhibits cyclooxygenase, which facilitates the production of thromboxane A2 (TA2). TA2 is a potent inducer of platelet aggregation and vasoconstriction. In humans, platelet cyclooxygenase can be completely inhibited with aspirin at doses as low as 30 mg daily. A study compared the use of aspirin with warfarin in the prevention of recurrent ischemic strokes: over a 2-year period, it was found that aspirin, as well as warfarin, protected against stroke recurrence and death (Mohr et al. 2001). Warfarin is prescribed for stroke recurrence prevention in many patients who have had an ischemic stroke. Therefore, aspirin is a reasonable, equally effective approach for some people, but for persons with artificial heart valves and certain types of atrial fibrillation, Coumadin has been shown to be more effective than aspirin in preventing stroke (Hurlen et al. 2002).
Other Conventional Platelet Aggregation Inhibition Drugs
There are a number of other drugs that act as platelet aggregation inhibitors, including dipyridamole, ticlopidine, and clopidogrel. As noted above, aspirin can provide comparable platelet aggregation inhibition and related risk reduction.
Derivatives of Coumarin (e.g., generics warfarin and dicumarol) interfere with the rate of synthesis of blood clotting factors II (prothrombin), VII, IX, and X. As a result, prothrombin and partial thromboplastin times are significantly altered by anticoagulants, but are not altered by antiplatelet agents such as aspirin. Patients taking Coumarin derivatives are monitored for PT and PTT times to optimize dosing and avoid excessive bleeding.
Coumadin (warfarin) is the most frequently prescribed drug for thrombosis prophylaxis (prevention). It is an anticoagulant drug that was originally isolated in 1939 from sweet clover. Interestingly, Coumadin is the active ingredient found in many commercial rat poisons and insecticides. It works by interfering with the synthesis of vitamin K-dependent coagulation factors. Coumadin is used as a prophylaxis for myocardial infarction, stroke, arterial thromboembolism, and deep venous thrombosis. It is also used in patients with prosthetic heart valves.
Coumadin prolongs both PT and APTT, but PT is the one used to guide treatment. However, the new standard is the International Normalization Ratio (INR) which is described below. Bleeding is the primary adverse effect of Coumadin therapy. Bleeding is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical state, and the use of other drugs that can affect blood coagulation or interfere with Coumadin metabolism.
Minor bleeding from Coumadin therapy usually begins with ecchymoses (purple patches on the skin). Then the mucous membranes are affected, causing epistaxis (nosebleed) and subconjunctival hemorrhage (bleeding under the mucous membranes covering the eyes and inner eyelids). Purple toe syndrome is also associated with Coumadin therapy. Hematuria (blood in the urine) may also occur. Major bleeding complications usually involve gastrointestinal (GI) and intracranial bleeding.
Coumadin has an extremely long list of contraindications and drug interactions (see the Cerebral Vascular Disease/Thrombotic Stroke protocol for a complete list). Of particular concern is its use in elderly patients because they are more susceptible to the effects of anticoagulants and have an increased risk of hemorrhage. Several common drugs interact with Coumadin, including acetominaphen, cimetidine, lovastatin, thyroid hormones, and estrogens and oral contraceptives.
Caution: Do not take aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (e.g., Motrin, Advil, Nuprin, etc.), ketop (e.g., Orudis, Orudis KT, Oruvail), naproxen (e.g., Naprosyn, Aleve, Anaprox), or other over-the-counter products while taking Coumadin, except under the supervision of your doctor. Over-the-counter NSAIDs increase the risk of bleeding. Consult your physician before taking any new prescription or over-the-counter product. Always take Coumadin in the evening, preferably between 5 p.m.-7 p.m.
Combining Coumadin with Antiplatelet Agents
As has been previously described, Coumadin interferes with specific coagulation factors that can induce a thrombotic event. Coumadin is classified as an "anticoagulant" agent.
Aspirin, fish oil, vitamin E, and garlic inhibit platelet adhesion and platelet aggregation and are classified as "antiplatelet" agents. The inhibition of blood platelets' ability to adhere and/or aggregate also decreases the likelihood of thrombosis.
In a perfect world, an individualized program would be designed to deliver the optimal combination of anticoagulation and antiplatelet agents to provide the broadest protection against thrombosis without inducing hemorrhage.
There is much debate and confusion about the interactions between dietary nutrients and prescription antithrombotic medications regarding clot formation. The concern expressed in some studies involves potential interactions between Coumadin and antiplatelet agents such as ginkgo biloba, green tea, vitamin E, garlic, and fish oil (Heck et al. 2000). There has been apprehension that certain supplements put the patient at risk for bleeding problems by adding to the overall effects of Coumadin.
As a result of this concern, some doctors advise patients who are taking Coumadin to avoid any dietary supplement that could possibly cause increased bleeding. A problem with this ultra-cautious approach is that it deprives the patient of nutrients they may need to sustain life. It also prevents the use of antiplatelet agents that act on hemostatic mechanisms, separate from those of Coumadin, to reduce more effectively the risk of thrombosis. There are major medical publications that confirm the importance of lowering the incidence of cerebrovascular stroke and heart attack by such a two-pronged approach using an agent with antiplatelet activity, for example, Coumadin (Fasey et al. 2002; Hurlen et al. 2002).
A patient taking Coumadin has to be concerned that any food, drug, nutrient, or other substance they put into their body may not only increase the bleeding time, but also affect Coumadin metabolism, which may either increase or decrease the effect of Coumadin on the International Normalized Ratio (INR). The inherent variability that occurs in each individual taking Coumadin makes it difficult to provide general guidance. For instance, the underlying medical condition determines the degree of desired anticoagulation. No studies have correlated optimal anticoagulant doses of Coumadin, as measured by the INR reference range, with optimal doses of multiple antiplatelet agents, as measured by the template bleeding time (TBT).
The template bleeding time is done in a physician's office where a template device nicks the skin and the number of minutes it takes for blood flow to stop is assessed by a nurse or lab technician. The "normal" template bleeding time is up to 9 minutes. A bleeding time (BT) of 4-5 minutes might indicate increased thrombotic risk, although a BT over 9 minutes may indicate an increased hemorrhagic risk. However, what is really important in this setting is the patient context, as discussed below.
As it relates to antiplatelet agents like fish oil and garlic, a BT of 4-5 minutes could suggest a benefit of taking higher amounts of these agents, whereas a BT over 9 minutes in a patient already on an antiplatelet agent might indicate that antiplatelet agent doses are having a biological effect and further dose increases should be avoided. The problem patients face today is that there are no standards that document the ideal balance between Coumadin and antiplatelet agents such as fish oil, garlic, vitamin E, etc. Too much Coumadin and/or antiplatelet agents can cause hemorrhage, whereas too little Coumadin and/or antiplatelet agent(s) can cause thrombosis. In this setting or context, as with many medical issues, balance is the key concept. The approach that the meticulous physician uses to achieve this balance is called "titration." There is an art to titrating doses to where the "happy medium" is reached. This is embraced in the key medical concept of therapeutic index which relates to the equation:
TI (Therapeutic Index) = Therapeutic Benefits ÷ SideEffects of Therapy.
In an ideal setting, a physician would carefully monitor the INR and the TBT to measure precisely the optimal level of anticoagulant and antiplatelet agents, respectively, in an individual patient. For instance, a patient with a heart valve replacement may have a desired INR range of 2.5-3.0, while an optimal template bleeding time may be between 7-9 minutes. If these tests were routinely conducted, a more scientific determination of the ideal intake of Coumadin, fish oil, garlic, vitamin E, etc. could be made.
Some early reports indicated that CoQ10 may reduce the anti-coagulant efficacy of Coumadin (Spigset 1994). These reports have been contradicted by a more recent study showing that CoQ10 does not affect Coumadin’s anticoagulation mechanisms (Engelsen et al. 2003).
Heparin inhibits thrombosis (clotting) via inactivating factor X and by inhibiting the conversion of prothrombin to thrombin. Activation of factor X is the major rate-limiting step in the coagulation cascade. By inhibiting the activation of the fibrin-stabilizing factor by thrombin, heparin prevents formation of a stable fibrin clot. Heparin also decreases the levels of triglycerides by releasing lipoprotein lipase from tissues. The resultant hydrolysis of triglycerides causes increased blood levels of free fatty acids.
Exanta® -- A Novel Drug on the Horizon
A new drug application for Exanta was filed with the FDA in the fourth quarter of 2003. Exanta (ximelagatran) is a novel drug with potential to revolutionize anticoagulant management. It is the first oral anticoagulant drug in over 50 years—since warfarin (Coumadin) — to reach late-stage clinical development. Current clinical trials are investigating the efficacy ximelagatran for treatment of venous thromboembolism and atrial fibrillation to prevent stroke. Ximelagatran is a specific, reversible, direct inhibitor of the clotting factor thrombin. It inhibits free and clot-bound thrombin and has a half-life of 1.7 to 2.5 hours (Samama et al. 2002). Ximelagatran has significant advantages: oral administration; minimal monitoring; active immediately; a short half-life; and no known pharmacokinetic food or drug interactions (Petersen et al. 2003). Because it has a predictable blood-thinning effect, the frequent monitoring and dose adjustments required for warfarin are not needed for ximelagatran. Its short half-life allows ximelagatran to be discontinued a few hours before surgery. Bleeding events are also low. Studies report impressive results:
* ESTEEM II (Efficacy and Safety of the Oral Thrombin Inhibitor Ximelagatran in Combination with Aspirin, in PatiEnts with REcent Myocardial Damage): ESTEEM II is a placebo-controlled, double-blind, multicenter (191 hospitals), multinational (18 countries) study that assessed 1883 patients with recent MI for 6 months. Study participants were given oral ximelagatran (24, 36, 48, or 60 mg) or placebo twice daily. All participants received aspirin (160 mg) daily. All-cause deaths, non-fatal MIs, and severe recurrent ischemia for ximelagatran and placebo were compared. After 6 months, oral ximelagatran combined with aspirin significantly reduced the risk of major cardiovascular events (24% compared to aspirin alone) with rare major bleeding events and no serious, clinically adverse outcomes related to the drug (Brown 2003; Wallentin et al. 2003).
* SPORTIF III (Stroke Prevention by ORal Thrombin Inhibitor in Atrial Fibrillation): SPORTIF III is a randomized, open-label, parallel-group study (3407 patients; 259 sites; 23 countries) to investigate ximelagatran as an alternative to warfarin to prevent thromboembolism and stroke in subjects with non-valvular atrial fibrillation (NVAF). In addition to NVAF, subjects had at least one additional stroke risk factor: previous MI, TIA, systemic embolism, hypertension, left ventricular dysfunction, age 75, or age 65 with coronary artery disease or diabetes mellitus. The objective was to establish the non-inferiority (as good as, no compromise) of ximelagatran compared to warfarin. Endpoints were incidence of stroke and systemic embolic events (death, MI, TIA, bleeding with treatment ended). Fixed-dose ximelagatran (36 mg) was given twice daily. Patients were treated for an average of 17 months. Twice-daily fixed-dose ximelagatran compared favorably with dose-adjusted warfarin in preventing stroke and systemic embolism events in AF. Despite lack of coagulation monitoring and the fixed-dose regimen, bleeding events were lower for ximelagatran than for warfarin, and there was no significant difference in all-cause mortality between the two treatment groups. The results of SPORTIF III suggest that ximelagatran can offer an alternative to warfarin and its complications without compromising patient safety or efficacy (Halperin et al. 2003; Saunders 2003).
* THRIVE III (THrombin Inhibitor in Venous Thromboembolism). THRIVE III is a double-blind, multicenter, randomized trial that enrolled 1233 patients who had received anticoagulant therapy for 6 months for venous thromboembolism. The patients were randomly assigned to receive extended secondary prevention of venous thromboembolism with 24 mg of oral ximelagatran (612) or placebo (611), twice daily for 18 months, with no monitoring of coagulation. Symptomatic recurrent venous thromboembolism occurred in 12 subjects in the ximelagatran group and in 71 subjects in the placebo group (all-cause death, 6 vs. 7; bleeding, 134 vs. 111; major hemorrhage, 6 vs. 5 with no fatalities). For individuals who discontinue anticoagulant treatment with warfarin after 6 months because the risk of bleeding outweighs the risk of recurrence, long-term treatment with ximelagatran offers clinically significant reduction of recurrent venous thromboembolism without coagulation monitoring and dose adjustments (Barclay 2003; Schulman et al. 2003).
Compared to warfarin, ESTEEM II, SPORTIF III, and THRIVE III studies all reported an increased incidence of elevated liver enzymes in the early months of ximelagatran treatment. The lowest dose of ximelagatran (24 mg) elevated liver enzymes in 6.5% of patients compared to placebo (1.2%). Elevations were seen in 12 to 13% of patients at higher doses (36, 48, 60 mg). Elevated enzyme levels were not associated with specific clinical symptoms and they decreased toward baseline levels as treatment continued or when it was discontinued (Brown 2003; Saunders 2003).
Arixtra® (fondaparinum, fondaparinux sodium) is another synthetic antithrombotic drug with a defined mechanism of action, specifically to inhibit factor FXa (a mediating factor in thrombin formation, the final factor in the blood clotting process). It has a half-life of about 17 hours. Fondaparinux inhibits free FXa, but not FXa bound to prothrombinase (Samama et al. 2002). Because Arixtra binds exclusively to only factor Xa which is essential to the clotting process, it ensures a highly predictable antithrombotic effect (Organon/Sanofi-Synthelabo 2002). Arixtra is the first synthetic antithrombotic drug used during hip fracture, hip replacement, or knee replacement surgery to reduce the risk of a pulmonary embolism (received FDA approval for hip fracture and hip and knee replacement surgery on December 7, 2001).
Laboratory Tests for Patient Response to Anticoagulants
* How PTs and INRs Are Calculated
It is extremely important to regularly evaluate a patient's response to Coumadin (or any other anticoagulant). This ensures that excess bleeding does not occur due to improper dosing of the medication. The standard blood test to assess coagulation status is the PT test using the INR as a standard unit of measurement. This blood test enables your physician to adjust the dose of Coumadin to provide optimal anticoagulation benefits without inducing serious bleeding.
The target INR for a person taking Coumadin varies depending on the type of disorder that puts the patient at risk for thrombosis. For some disorders, the ranges are between 1.6-2.5, although others may extend up to 3.5. Although test results can vary considerably between individuals, the INR becomes a very important number to evaluate. If, for instance, you significantly overcoagulate and your INR levels significantly exceed 4.5, your physician can prescribe vitamin K to bring your INR levels into a safe range. Some physicians fail to prescribe vitamin K and just tell the overcoagulated patient to stop the Coumadin. Failing to prescribe vitamin K during an acute overcoagulation state (INR over 4.5) puts a patient in serious jeopardy.
Additionally, as noted earlier, if you are taking an anticoagulant drug such as Coumadin or heparin, you must be very careful about what you eat and what medicines you take as well as being diligent about having your blood checked regularly. This is even more essential if you take a combination of drugs for other conditions or take over-the-counter medications such as aspirin. With the concomitant use of natural therapies and aspirin, the need for weekly or biweekly blood monitoring increases even more. The two most important markers or references to monitor for those taking other drugs and/or antiplatelet agents with Coumadin are the INR reference range and the TBT test.
For those taking Coumadin, prothrombin blood tests using the INR reference ranges are recommended weekly or biweekly. For those with serious diseases such as cancer, in addition to using INR reference ranges, the following supplementary blood tests might be considered every 30-90 days to measure thrombotic risk more precisely:
* D-dimer of fibrin
How PTs and INRs Are Calculated
When a fibrin clot forms, the time measured in seconds is referred to as the prothrombin time (PT). Thromboplastin agents used for testing come from various sources with varying degrees of sensitivity. This is important information because the result can have a detrimental effect on the management of the anticoagulant therapy.
To standardize potential differences in sensitivity between reagents, manufacturers assign an International Sensitivity Index (ISI) to each batch of reagent. The ISI is then compared to a working reference reagent preparation. The INR is a mathematical calculation that corrects for the variability of PT results due to the variable sensitivities of the thromboplastin agents used by various laboratories.
INR = (patient PT/control PT) ¥ ISI (International Sensitivity Index)
Continued . . .
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