Risky Combos

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Risky Combos?

• What you need to know about the combination of
  Anti-coagulants and Anti-platelets and FOOD and
  HERB interactions

Trudy Arbo, PharmD, BCPS Debbie Blais,
RD Atlantic Chronic Disease Congress May 22,
2009
2
Objectives

• Discuss the prevalence of using herbal products
  and supplements in the Canadian population
• Provide learner with overview of the role of
  anti-platelets and anticoagulants in cardiac care
• Illustrate clinically significant interactions
  between these medications and food and herbal
  supplements
• Provide learner with practical tips to manage
  patients using both agents
• Discuss expected outcomes when these combinations
  occur

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How many people use Herbal Products?

• 18 of population use herbals on a regular basis
• 5 million people in Canada and 35 million in the
  US
• Up to 50 of Canadians use a herbal product every
  year (not regular use)
• Of the regular herbal product users 50 feel they
  are important to their health and wellbeing
• BUT only 1/3 told their health care provider
  about use

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• NOT the patient that is dissatisfied with
  traditional medicine
• NOT the patient with an unrealistic search for a
  cure
• It is the patient with an increased likelihood to
  seek out preventative care services

Geil, P On the the Cutting Edge 2008, 29617-620
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Blood Clot
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Coagulation

• Clotting
• Activation of clotting cascade
• Clotting Factors involved
• Factors I to XIII
• E.g. thrombin, fibrin

• Anticoagulation
• Balance of the clotting cascade
• Includes anti-thrombin III, Protein C and S,
  Plasminogen and other factors

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Coagulation

• Reasons for clotting
• Virchows Triad
• Abnormalities in blood flow
• Bed rest, immobility, etc
• Abnormalities in clotting
• Malignancy, pregnancy, deficiencies in ATIII,
  protein C and protein S
• Abnormal vascular surfaces
• Catheters, vascular injury, trauma

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Coagulation Made Easy

• Initiation of clotting cascade
• Platelet activation and aggregation
• Activation of Intrinsic pathway or Extrinsic
  pathway or both
• Extrinsic Pathway is activated
• Due to damaged tissue
• Intrinsic Pathway is activated
• Due to trauma to the blood itself
• Common pathway is activated
• Thrombin is formed
• Converts fibrinogen to fibrin
• NET RESULT Clot formation

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Anticoagulation Agents

• Heparin
• LMWH
• Warfarin
• Anti-coagulants
• thrombolytics
• ASA and Clopidogrel
• Anti-platelets

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Warfarin works here
LMWH works here
Heparin works here
Lytics works here
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Anticoagulant Agents

• Warfarin
• Inhibits coagulation by inhibiting vitamin
  K-dependent clotting factors (II, VII, IX and X)
  as well as proteins C and S
• It takes several days for maximum anticoagulation
  effect to be realized
• Estimated at 5 days for most patients
• Monitoring
• International Normalizing Ratio (INR)
• Anticoagulation may be reversed by administration
  of vitamin K (oral or SC routes recommended)

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INR

• International normalizing ratio (INR)
• Ratio of PT compared to control
• Evaluates vitamin K dependent clotting factors
• Factor II, VII, IX, X
• Used for monitoring warfarin therapy
• LMWH and heparin has no effect on INR
• Normal Reference range 0.8 to 1.2

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Half lives of Clotting Factors

• Factor VII, Protein C and S
• 5 to 6 hours
• Shortest half life and has biggest impact on INR
• Factor IX
• 24 hours
• Factor X
• 40 hours
• Factor II (prothrombin)
• 60 hours
• This is the real target of warfarin therapy

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Monitoring INR

• The INR has a delayed correlation with the
  warfarin dose given
• Due to the inhibition of vitamin K clotting
  factors
• e.g. Todays dose of warfarin
• 50 will affect tomorrows INR
• 75 will affect the next days INR

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Common Indications for Warfarin

• Venous Thromboembolism (PE/DVT)
• Target INR 2.5 (range 2-3)
• Atrial fibrillation
• Target INR 2.5 (range 2-3)
• Mechanical heart valve (not bioprosthetic)
• Target INR 3.0 (range 2.5-3.5)

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Other Reasons for Warfarin

• CHF with severe LV dysfunction
• INR target 2.5 (range 2-3)
• Anterior myocardial infarction
• For three months post
• Antiphospholipid antibody syndrome
• Target 3.0

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Side Effects

• Bleeding
• Minor bleeding (up to 20)
• Nose-bleeds, minor cuts,
• Bruising
• Major bleeding (5)
• GI bleed, Intracranial bleed
• Any hemodynamic instability
• Predisposing factors
• CHF, liver disease, peptic ulcer disease,
  advanced age, malnutrition, alcohol use, aspirin
  use, malignancy

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Anti-Platelet Agents

• Aspirin
• Inhibits platelet aggregation through inhibition
  of cyclooxygenase
• Reduces the production of Thromboxane A2
• Also reduces prostaglandin production
• Clopidogrel (Plavix)
• Inhibits adenosine diphosphate (ADP)-induced
  platelet aggregation
• NET RESULT Platelet aggregation inhibition

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Potential Herbal Interactions
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Herbal Product Interactions

• Dan-Shen (Red Sage)
• Echinacea
• Feverfew
• Garlic
• Gingko
• Ginger
• Green tea
• All of these medication should be avoided if
  patient is started on Warfarin

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Dan-Shen (Red Sage)

• Uses
• Coronary heart disease, supplement post surgery
• Proposed mechanism of interaction
• Affects INR by increased warfarin elimination
• Platelet aggregation
• NET Effect increased risk of bleeding
• Level of evidence
• Case reports

http//chinesemedicinenews.com/wp-content/uploads/
2007/06/dan-shen4.jpg
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Echinacea Purpurea

• Uses
• Stimulates immune response to infections
• Potential mechanism of interaction
• Increases INR by decreasing warfarin metabolism
  by CYP3A4 liver enzyme
• Level of evidence
• Potential

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lower.jpg
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Feverfew

• Uses
• Migraine, rheumatoid arthritis
• Potential Mechanism of interaction
• risk of bleed by platelet aggregation
• Level of Evidence
• potential

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Garlic supplements (NOT FOOD)

• Uses
• Atherosclerosis, hypertension
• Potential Mechanism of interaction
• risk of bleed by platelet aggregation
• Level of evidence
• case reports

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ploads/garlic_tight.jpg
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Ginger

• Uses
• Nausea
• Potential Mechanism of Interaction
• risk of bleed by platelet aggregation
• Level of Evidence
• Potential

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Ginkgo Biloba

• Uses
• Dementia
• Potential Mechanism of Interaction
• risk of bleed by platelet aggregation
• Level of Evidence
• case reports

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herb/product3.jpg
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Ginseng

• Uses
• Stress, physical endurance
• Potential Mechanism of interaction
• INR, unknown mechanism (case reports)
• Level of Evidence
• Case reports

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What about CoEnzyme Q10?

• Potential interaction
• May reduce effectiveness of warfarin
• May be due to structural similarities with
  vitamin K
• Conflicting reports
• Likely okay if patient taking regular dose
• Concern with stopping and starting

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Green Tea
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Green Tea

• Growing evidence suggesting that tea may protects
  from certain cancers including breast cancer.
• Yes-! Healthful properties of tea are largely
  attributed to polyphenols
• Yes -! Green tea has the highest polyphenol
  content and the lowest caffeine compared to
  oolong or black tea
• Buteven small amounts have been shown to cause a
  decrease in INR, which means patient may
  experience blood clotting problems.
• Take advantage of the teachable moment!

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Garlic as a food source

• There is some evidence for Cardioprotection
• Related to Lipids and potentially blood pressure
  lowering effects
• Garlic contains different sulfur compounds
• S-allyl cystein (SAC) has been shown to lower LDL
  
• cholesterol by up to 11.5.
• Also seems to have a modest anti-hypertensive
• benefit in lowering blood pressure by 5-7.
• Take advantage of a teachable moment!
• In general, garlic cloves ingested in diet is
• considered safe for warfarin users

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Cranberry Juice and Tablets

• Popular drink and used to help prevent UTIs
• Interaction with warfarin is due to flavenoids in
  the juice which are known to inhibit cytochrome
  P450 enzymes
• NET RESULT May increase INR
• Cranberry juice and dried capsules should limited
  while on warfarin

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• Should patients take EPA/DHA?
• What are considered safe doses?

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Fish Oils

• Fish oils
• Containing EPA (eicosapentaenoic acid)
• Alters platelet aggregation and decreases levels
  of factor VII
• Level of Evidence
• Case reports in doses gt 2 g per day

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EPA Recommendations

• Use with caution if on warfarin, clopidogrel
  (Plavix) or ASA
• Excessive amounts (gt 2 grams/day) of EPA may
  increase risk of bleeding
• 1 g/day considered heart healthy

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Vitamin K containing food and Warfarin

• TAKE HOME MESSAGE As long as patients diet
  remains consistent and INRs are within target
  range and not difficult to control IT IS not
  worrisome
• Only when patient drastically changes diet,
  increases green leafy vegetables, stops eating
• Then INR should be taken more frequently to
  ensure adequate anticoagulation
• Also a consideration in patients with difficult
  to control INRs

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Vitamin K food sources

• Common High Sources of vitamin K
• Dark green leafy vegetables such as
• Spinach, kale, turnip greens, beet greens,
  mustard greens, brussel sprouts, broccoli,
  parsley, fiddleheads, lettuce
• Liver
• Dulse
• Green Tea
• Main thing to remember is consistency in diet day
  to day

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• Is any amount Safe?
• Consistency and Moderation are essential
• 1-2 drinks/day does not appear to influence the
  anticoagulation effect of warfarin
• Excessive consumption beyond two drinks/day tends
  to INCREASE INR

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• Define What One Drink is....
• 12 ounce bottle of beer
• 5 ounces of wine
• 1.5 ounces of spirits

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Possible Herbal Interactions with Anti-Platelet
therapy

• THREE BIG Gs Gingko, Garlic, Ginseng
• Feverfew
• Fish oils (with EPA)
• Proposed mechanism of action
• Further platelet inhibition
• Level of evidence
• Theoretical
• Other Considerations
• Alcohol potential for gastric mucosal damage

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Take home message

• Warfarin therapy
• If INR consistent and patient eating a regular
  source of vitamin K containing food
• No concern
• If INR difficult to control or patient is
  experiencing bleeding complications (minor),
  consider evaluating food and medication sources
  to minimize variability
• Herbal Products are not well studied and may lead
  to further complications
• Not recommended for use in patients on warfarin
  therapy
• Anti platelet therapy
• No specific dietary considerations
• Avoid use of herbal products that further alter
  platelet function

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Questions?
Thank you!
Questions?
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References

• http//www.vhpharmsci.com/Newsletters/1990s-NEWS/A
  rticle21.htm
• Rose KD et al. Spontaneous spinal epidural
  hematoma with associated platelet dysfunction
  from excessive garlic ingestion a case report.
  Neurosurgery 199026880-2.
• Burnham BE. Garlic as a possible risk for
  postoperative bleeding. Plast Reconstr Surg
  199595211.
• German K et al. Garlic and the risk of TURP
  bleeding. Br J Urol 199576518.
• Rowin J et al. Spontaneous bilateral subdural
  hematomas associated with chronic Ginkgo biloba
  ingestion. Neurology 1996461775-6.
• Gilbert GJ. Ginkgo biloba. Neurology
  1997481137.
• Rosenblatt M, Mindel J. Spontaneous hyphema
  associated with ingestion of Ginkgo biloba
  extract. N Engl J Med 19973361108.
• Matthews MK. Association of Ginkgo biloba with
  intracerebral hemorrhage. Neurology
  1998501933-4.
• Vale S. Subarachnoid haemorrhage associated with
  Ginkgo biloba. Lancet 199832536.
• Tam LS et al. Warfarin interactions with Chinese
  traditional medicines danshen and methyl
  salicylate medicated oil. Aust NZ J Med
  199525258.
• Yu CM et al. Chinese herbs and warfarin
  potentiation by Danshen. J Intern Med
  1997241337-0.
• Izzat MB et al. A taste of chinese medicine! Ann
  Thor Surg 199866941-2.
• Janetzky K et al. Probable interaction between
  warfarin and ginseng. Am J Health-Syst Pharm
  199754629-3.
• Cadario B. The bottom line on herbal products. BC
  Pharmacy June 1998.
• Miller LG. Herbal medicinals. Selected clinical
  considerations focusing on known or potential
  drug-herb interactions. Arch Intern Med
  19981582220-11.
• Briggs C. Alfalfa. Can Pharm J 199412784-85,
  115.
• Burnham BT (ed). The review of natural products.
  St. Louis Facts and Comparisons1992. Betel Nut,
  Dong quai.
• Hoult JRS et al. Pharmacological and biochemical
  actions of simple coumarins natural products
  with therapeutic potential. Gen Pharmacol
  199627713-22.
• Chan K et al. The effects of Danshen (Salvia
  miltiorrhiza) on warfarin pharmacodynamics and
  pharmacokinetic of warfarin enantiomers in rats.
  J Pharm Pharmacol 199547402-6.