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Cerebral Vascular Disease
Low-Dose Aspirin
Low-dose aspirin is the antiplatelet agent of choice for stroke prevention. Doses of 160-325 mg daily administered within 48 hours of stroke onset have been shown to significantly reduce the risk of recurrent stroke during the first 2 weeks and possibly improve outcome at 6 months (CASTCG 1997; IST 1997). The Second European Stroke Prevention Study reported risk reductions for aspirin treatment, when compared with a placebo, to be as high as 27.6% (Sivenius et al. 1999).
Aspirin has shown such a potent effect in preventing strokes that the use of anticoagulants such as heparin to treat ischemic strokes decreased from 1985-1990, whereas the use of aspirin increased by more than 50% as reported in the Minnesota Stroke Survey, reported in the Journal of Stroke and Cerebral Diseases (McGovern et al. 1996).
An article in the journal Thrombosis Research described a study on patients who had survived a stroke or TIA. The research showed that the use of a low-dose aspirin (50 mg) reduced the incidence of stroke by 18-28% when study participants consumed aspirin over a period of time (Investigators 1998).
One of the main side effects of aspirin is unwanted bleeding. Tinnitus can also occur at high doses (Day et al. 1989). Aspirin is contraindicated for those at high risk of hemorrhagic stroke. Many health-oriented people are taking aspirin in combination with natural platelet aggregation inhibitors including vitamins C and E, bromelain, garlic, ginkgo biloba, curcumin, St. John's wort, green tea, policosanol, vinpocetine (periwinkle), and fish oils. It is important to monitor template bleeding time to ensure stable blood thinning effects are consistent while avoiding fluctuations in platelet aggregation that may increase the risk of hemorrhagic stroke. The template bleeding time test is described later in this protocol.
Aspirin is considered by many to be a miracle drug and may have many undiscovered health benefits. Aspirin inhibits prosta n glandin E2 and C-reactive protein, both of which have been linked to many chronic inflammatory conditions (Ikonomidis et al. 1999).
Warfarin
Warfarin (Coumadin) is the most commonly prescribed drug for thrombosis prophylaxis (prevention) in very high-risk individuals. Its uses include prophylaxis for myocardial infarction, stroke, arterial thromboembolism, and deep venous thrombosis. Warfarin is also used in patients with prosthetic (artificial) heart valves.
Warfarin was originally isolated from sweet clover in 1939. It is the active ingredient in commercial rat poison and insecticide. Warfarin interferes with the synthesis of vitamin K which forms several essential coagulation factors. Warfarin prolongs prothrombin time (PT) and thromboplastin time (APTT). Prothrombin time is used to guide treatment. The International Normalization Ratio (INR) is becoming the new standard to monitor anticoagulation treatment.
Side-Effects and Contraindications for Warfarin
Bleeding is the primary adverse effect of warfarin therapy and is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical state, and the use of other drugs that may affect blood coagulation or interfere with warfarin's metabolism.
- Minor bleeding complications include bleeding from mucous membranes, subconjunctival hemorrhage (bleeding under the mucous membranes covering the eyes and inner eyelids), hematuria (blood in the urine), epistaxis (nosebleed), and ecchymoses (purple patches on the skin).
- Major bleeding complications include bleeding from the gastrointestinal tract, intracranial bleeding, and retroperitoneal bleeding. Massive hemorrhage usually involves the gastrointestinal tract, but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites.
Warfarin (Coumadin) has an extremely long list of contraindications and drug interactions (see below). Of particular concern is its use in elderly patients because they are more susceptible to the effects of anticoagulants and have an increased possibility of hemorrhage.
- Warfarin is contraindicated in alcoholism, aneurysm, breast-feeding, the elderly, endocarditis, hemophilia, hemorrhage, hepatic disease, hypertension, intramuscular injections, leukemia, lumbar puncture, peptic ulcer disease, pericardial effusion, polycythemia vera, pregnancy, protein C deficiency, protein S deficiency, psychosis, surgery, vasculitis, vitamin C deficiency, and vitamin K deficiency.
- Warfarin interacts with a large number of common drugs, including acetaminophen, aspirin, barbiturates, some antibiotics, estrogens, ethanol, heparin, influenza virus vaccine, lovastatin, NSAIDs, oral contraceptives, thrombolytic agents, and thyroid hormones. Your physician must be informed of all prescription and over-the-counter medications you are taking before beginning warfarin therapy.
- Adverse side effects to warfarin include agranulocytosis, alopecia (hair loss), anorexia, bone loss, bleeding, chondrodysplasia punctata, cleft palate, diarrhea, exfoliative dermatitis, fetal abortion, intracranial hemorrhage, intraocular hemorrhage, leukopenia, nausea/vomiting, pruritus (itching), purple-toe syndrome, skin necrosis, and urticaria.
- Warfarin may interact with natural platelet aggregation inhibitors including those mentioned earlier for aspirin. It is important to monitor template bleeding times to ensure stable blood thinning effects are consistent with supplementation to avoid fluctuations in platelet aggregation.
Combining Coumadin with Antiplatelet Therapies
A patient taking Coumadin has to be concerned that any food, drug, nutrient, or other substance that he puts into his 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 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 blood test) with optimal doses of multiple antiplatelet agents (as measured by the template bleeding time [TBT]). The TBT is done in a physician's office. 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, while a bleeding time over 9 minutes may indicate an increased hemorrhagic risk. However, what is really important in this setting is the patient.
As it relates to antiplatelet agents such as 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, and so forth. Too much Coumadin or antiplatelet agents can cause hemorrhage, whereas too little Coumadin or antiplatelet agents can cause thrombosis. In this context, as with many medical issues, balance is the key concept. The approach that a meticulous physician uses to achieve this balance is called titration. There is an art to titrating doses to a point where the happy medium is reached.
In an ideal setting, a physician would carefully monitor the INR and the template bleeding time to precisely measure 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, and other supplements could be made.
An example of why prothrombin time (the result is presented as an INR) and template bleeding time testing are so important can be seen in a scenario of a patient taking Coumadin for one medical problem while at the same time using nutrients such as coenzyme Q10 (CoQ10) and fish oil for other medical conditions. A person who has congestive heart failure (a common complication with valve replacement) may require supplemental CoQ10 to improve cardiac function, for example, cardiac output. CoQ10 enhances the energy-producing organelles called mitochondria to more effectively produce energy within heart muscle (Rosenfeldt et al. 2002). Coumadin is being utilized to prevent a clot from forming on the donated heart valve which could break off, enter the blood circulation, and lead to a cerebral vascular accident (CVA)--what is commonly called a stroke.
In this same patient, CoQ10 is being used to optimize heart muscle performance to improve the heart's function as a pump. CoQ10 is also helping this patient by preventing oxidation of LDL cholesterol which is felt to be part of the pathogenesis of vascular disease. In the context of this patient, the valve replacement surgery inflicts massive trauma on the body that can result in a chronic systemic inflammatory syndrome. High-dose fish oil and gamma-linolenic acid (GLA) can help suppress pro - inflammatory cytokines that are the underlying causes of so much degenerative disease. If periodic TBT tests are performed and Coumadin dosing is being properly titrated via the INR, then one can optimally adjust the antiplatelet agent (fish and borage oil) dose to guard against excess bleeding. The TBT test combined with the INR test would theoretically enable patients to take supplements they may need to sustain life (CoQ10), optimize the use of Coumadin, and reduce the risk of hemorrhage. The end result is therapy with an improved therapeutic index for the patient. This is an example of how listening to the biology of vital processes can enhance the quality and quantity of life.
Ticlopidine
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 value as an alternative to aspirin. Ticlopidine is often considered in patients that have a high risk of thrombotic stroke and are intolerant of aspirin.
- Ticlopidine is contraindicated in blood disorders such as hemorrhage, coagulopathy, intercranial hemorrhage, neutropenia, and thrombocytopenia. It is not used before surgery. Ticlopidine is also contraindicated in hepatic (liver) disease and hypercholesterolemia.
- Ticlopidine has drug reactions with antacids, anticoagulants, aspirin, cimetidine, cyclosporine, digoxin, theophylline and thrombolytic agents.
- Ticlopidine has a large number of side effects, including agranulocytosis, anemia, arthropathy, cholestasis, diarrhea, dyspepsia, elevated hepatic enzymes, hemolysis, hepatitis, hypercholesterolemia, hyponatremia, interstitial pneumonitis, jaundice, nausea or vomiting, nephrotic syndrome, neutropenia, pancytopenia, peripheral neuropathy, pruritus, purpura, serum sickness, throm-bocytopenia, thrombotic thrombocytopenic purpura (TTP), and urticaria vasculitis.
An analysis of 18 trials documented a 23% reduction in stroke risk with antiplatelet agents. The drug ticlopidine was found to be the most effective antiplatelet agent, but its adverse side effects frequently restrict its long-term use (Albers 1995).
A review of clinical trials compared aspirin and ticlopidine. Ticlopidine was found to be modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk, but there is uncertainty about the size of the additional benefit. Ticlopidine was associated with less gastrointestinal hemorrhage and other upper gastrointestinal upset than aspirin, but commonly had side effects of skin rash and diarrhea. Ticlopidine was also associated with developing side effects of neutropenia and thrombotic thrombocytopenic purpura (Hankey et al. 2000).
Cholesterol-Lowering Drugs
Studies have found that statin drugs (HMG-CoA reductase inhibitors) may be of benefit in reducing the incidence of ischemic stroke for patients with established coronary artery disease (Furberg 1999; Vaughan et al. 1999; Vaughan et al. 2001a; 2001b). Unfortunately, these trials have shown a reduction in risk of stroke only in patients enrolled in studies for coronary artery disease. Studies have not been done for primary stroke prevention or in patients without coronary artery disease. In patients with previous myocardial in-farction and cholesterol levels lower than 240 mg/dL, pravastatin reduced the risk of stroke by 31%, compared with placebo (Sacks et al. 1996). The beneficial effects of statin drugs in stroke prevention may be due to several mechanisms, including:
- Lowering LDL cholesterol levels
- Anti-inflammatory and antithrombotic actions of statins that occur within the blood and in plaque
- Protecting against cerebral ischemia through beneficial modulation of the brain endothelial nitric oxide system. Statins both up-regulate endothelial nitric oxide synthase (eNOS) and inhibit inducible nitric oxide synthase (iNOS), effects that may protect the nervous system.
A study examined the protective effects of Mevacor ( mevastatin lovastatin ) in male mice. Mevastatin (2 mg/kg or 20 mg/kg a day) was administered to male mice for 7, 14, or 28 days before inducing a middle cerebral artery occlusion. Lo Me vastatin increased levels of endothelial nitric oxide synthase mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. The greatest protection was seen with 14- and 28-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced after only 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment (Amin-Hanjani et al. 2001).
Mevacor ( lo me vastatin) and other statin drugs used to lower cholesterol are available by prescription.
Novel Factors that Contribute to Primary or Secondary Stroke
Homocysteine
Homocysteine, an intermediate molecule formed from methionine, has been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke. Elevated homocysteine levels are found in 20-40% of patients with heart disease. Elevated homocysteine is present in as many as 50% of patients with stroke. Measuring and reducing homocysteine levels is an important preventive highly recommended by the Life Extension Foundation since as early as 1981 (more than a decade before it was recognized by conventional medicine) (Selhub et al. 1998; Boden-Albala et al. 2000; Hankey et al. 2001).
The exact mechanism by which homocysteine promotes arteriosclerosis is currently being investigated. Several mechanisms have been proposed (Sarkar et al. 1999):
- Homocysteine accumulates in endothelial cells causing endothelial dysfunction and injury, followed by platelet activation and thrombus formation.
- Homocysteine stimulates the proliferation of smooth muscle cells which line arteries, a central component in atherogenesis.
- Homocysteine induces endothelial cell injury due to the generation of hydrogen peroxide which damages endothelial cells, exposing the underlying cell matrix and smooth muscle cells. This, in turn, promotes the activation of platelets and leukocytes to repair the injury (the blood clotting system).
- Homocysteine increases nitric oxide production by activating transcription factor NF.
- Homocysteine leads to an overproduction of oxidative radicals (reactive oxygen species) that cause lipid peroxidation and oxidation of LDL cholesterol. These oxidized lipids form dense particles which are consumed by macrophages that create foam cells that accumulate in plaques on the endothelial cells lining arteries.
- Homocysteine also interferes with DNA repair which makes the blood vessels less pliable and more susceptible to plaque buildup.
Dr. Kilmer McCully (1996) reported that homocysteine plays a key role in every pathophysiological process that leads to arteriosclerotic plaque. Some consider homocysteine to be much worse than cholesterol.
Homocysteine, although toxic itself, is normally metabolized into other nutrients that are beneficial to the body, including cysteine, taurine, and glutathione. Several natural supplements (including vitamin B6, vitamin B12, folic acid, zinc, and methyl donors such as trimethylglycine, SAMe, and choline) are needed for homocysteine metabolism.
While it does make sense to take supplements that contain these important nutrients, one should not automatically assume that their homocysteine levels are fine without a specific laboratory test. For more information about homocysteine, see the Homocysteine and Hypertension sections of the Cardiovascular Disease protocol and the Hypertension protocol. |