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Thrombosis Prevention

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:

• PTT
• Fibrinogen
• 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)

THROMBOTIC RISK FACTORS

• Homocysteine
• Fibrinogen
• Atherosclerosis
• Inflammation
• Lipoprotein(a)
• Hypothyroidism

Homocysteine
Homocysteine is a toxic compound formed in the body from the amino acid methionine. Several studies have shown that homocysteine increases blood coagulation by inhibiting tissue fibrinogen activators. The result is increased levels of fibrinogen and fibrin (de Jong et al. 1998; Selhub et al. 1998; Coppola et al. 2000; Durand et al. 2001; Kuch et al. 2001).

In order to reduce blood homocysteine levels, adequate amounts of folic acid, vitamin B12, and vitamin B6 are usually required. High homocysteine levels have been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke. Ideal levels of homocysteine are under 7 micromoles/L of blood.

For more information about homocysteine, see the Cardiovascular Disease protocol.

Fibrinogen
Fibrinogen is the precursor to fibrin, a coagulant protein that binds platelets together to form a blood clot. It has a role in normal and abnormal clot formation (coagulation) in the body. During coagulation, fibrinogen reacts with thrombin, releasing four small fibrinopeptides that produce fibrin, which in turn creates an insoluble fibrin network generally referred to as a scab.

Fibrinogen also participates in the cellular phase of coagulation. Fibrinogen promotes platelet aggregation, which can lead to diminished blood flow and reduced delivery of oxygen to the body. Fibrinogen can also cause blood platelets to bind together, initiating abnormal arterial blood clots.

An article in the journal Neurology described a study of cardiovascular laboratory tests in 136 patients with acute stroke, 76 patients with comparable risk factors for stroke, and 48 healthy controls. Statistical analysis found that prior stroke and fibrinogen levels predicted new events in stroke patients. After 1 year, fibrinogen levels remained elevated in stroke survivors. The researchers concluded that fibrinogen levels are associated with increased risk of recurrent vascular events (Beamer et al. 1998).

The Life Extension Foundation recommends the measurement of fibrinogen as part of a cardiovascular risk assessment. The normal reference range for fibrinogen is 200-400 mg/dL. Optimally, fibrinogen should be 200-300 mg/dL.

Atherosclerosis
Once symptomatic atherosclerosis has developed, a person is at significant risk for stroke, heart attack, and peripheral arterial occlusion. The occlusive event (stroke, MI, etc.) tends to develop at sites of preexisting narrowing (stenosis). Atherosclerotic plaques can rupture and expose tissue factor-rich plaque contents to the blood, initiating thrombus formation.

Inflammation
Chronic inflammation is associated with a variety of chronic diseases, including cardiovascular disease. C-reactive protein (CRP) is a sensitive indicator of inflammation that rises before the erythrocyte sedimentation rate. CRP is a marker of systemic inflammation and unstable arterial plaque, both of which are indictors of increased thrombotic risk. Certain pro-inflammatory immune cytokines cause elevated CRP. These cytokines may be suppressed by taking supplements such as the DHA fraction of fish oil, the hormone DHEA, vitamin K, and nettle leaf extract.

An article in the journal Thrombosis Research described a study of patients with acute thrombotic stroke prior to treatment. The patients with elevated CRP also had significantly elevated plasma levels of thrombin-antithrombin complex, plasmin-antiplasmin complex, and d-dimer of fibrin. When compared to those with normal levels, platelet aggregation induced by ADP was also significantly higher in patients with elevated CRP. The authors hypothesized that the activation of the blood coagulation and platelet aggregation system may be related to elevated CRP levels in stroke patients (Tohgi et al. 2000). A feature article in the May 2002 issue of Scientific American further emphasized the link between chronic inflammation and the evolution of atherosclerosis and coronary artery disease (Libby 2002).

Measuring CRP levels (using a high-sensitivity C-reactive protein blood test) is highly recommended by the Life Extension Foundation (see Table 2 for the normal and optimal range of CRP).

Lipoprotein(a)
Lipoprotein(a) is an altered form of LDL cholesterol that has a structure nearly identical to plasminogen, a protein that forms plasmin. Plasmin dissolves fibrin. Unfortunately, lipoprotein(a) inhibits the breakdown of fibrin by competing with plasminogen. Lipoprotein(a) was found to be a key component in blood clots, plaque formation and coronary heart disease (CHD) (Rath et al. 1989; Beisiegel et al. 1990).

Linus Pauling's theory of heart disease focused on the adverse effects of lipoprotein(a) on the cardiovascular system. Pauling and Rath proposed that lipoprotein(a) acted as a surrogate (replacement) for vitamin C (Rath et al. 1990a). They also proposed that a deficiency of vitamin C resulted in the increased production of lipoprotein(a), which both hardened the arteries and caused blood clots (Rath et al. 1990b). Linus Pauling recommended the use of high doses of pure vitamin C and lysine to both prevent and treat cardiovascular disease. Niacin, CoQ10, serine, and regular aerobic exercise have also been shown to lower lipoprotein(a) (Cohn 1998; Singh et al. 1999; Batiste et al. 2002).

Hypothyroidism
The endocrine system is a complex mechanism in which each organ impacts the function of other organs. A low-functioning thyroid (hypothyroidism) would therefore impact other systems, including the cardiovascular system. Hypothyroidism is associated with increased cholesterol levels, atherosclerosis, and increased homocysteine (Carantoni et al. 1997; Diekman et al. 1998; Nedrebo et al. 1998; Hussein et al. 1999; Hak et al. 2000; Kahaly 2000; Diekman et al. 2001). The effect of hypothyroidism on the blood clotting system is currently controversial and is the focus of several studies (Chadarevian et al. 1998; Muller et al. 2001).

For additional information about hypothyroidism, see the Thyroid Replacement Therapy protocol.

COMPREHENSIVE LABORATORY TESTING FOR CARDIOVASCULAR RISK

The Life Extension Foundation recommends that all of its members be checked for cardiovascular risk with both conventional laboratory tests and new markers such as CRP.

Furthermore, optimal ranges of these laboratory tests are much narrower than the standard reference ranges used in conventional medicine. It is important to emphasize that the "average" person has a high risk of developing a thrombotic-related disease. For health-conscious people, this dismal fate is unacceptable.