8/98 Dr. David Martin

"Probucol and Multivitamins in the Prevention of Restenosis after Coronary Angioplasty"

The 8/7/97 NEJM article "Probucol and Multivitamins in the Prevention of Restenosis After Coronary Angioplasty" was a double blind study in 200 patients evaluating restenosis rates following balloon coronary angioplasty.

Results:	Probucol	Probucol + MV	MV	Placebo
% restenosis	20.7	28.9	40.3	38.9
% repeated angioplasty	11.2	16.2	24.4	26.6

1.  
2. The study was based on previous conflicting studies with the use of b-carotene or tocopherols or vitamin C reducing oxidative stress-induced lipid peroxidation associated with percutaneous transluminal coronary angioplasty.
3. In the author's own admission the large doses of vitamins used could paradoxically be prooxidant.

   Doses used:

   60,000 IU provitamin A

   1,400 IU vitamin E (as dl alpha-tocopherol)

   1,000 mg vitamin C

   Administered 30 days before and 180 days after.

4. There was no statistical evidence of drug interaction between probucol and MV.
5. Probucol is poorly absorbed and requires 3 to 4 months to reach steady state -- in previous studies with short-term therapy probucol failed. It was interesting that the authors didn't start probucol at least 90 days prior!

 

The following interactions are possible when Coumadin is administered concurrently with MV or Probucol:

1. If the patient is vitamin K deficient or predisposed to vitamin K deficiency, i.e. long-term cephalosporins, doses of vitamin E over 400 IU units per day has been shown to further reduce vitamin K dependent coagulation factors II, VII, IX, and X. This has not been demonstrated in patients or animals with normal vitamin K status.
2. Coumadin is highly bound to albumin 97-99% and may be displaced by other medications or procedures/malnutrition etc. resulting in hypoalbuminemia resulting in more free "active" drug.
3. Both Coumadin and Probucol are metabolized by hepatic micosomal enzymes and may induce or retard clearance of either one -- no studies have been done.

 

INTERPRETATION (specific consideration with Genesis Vitamins)

1. Genesis vitamins contain 400 IU of vitamin E, 6 mg betacarotine, 1,000 IU vitamin A and 500 mg vitamin C. The majority of patients could continue before, during and after probucol and/or Coumadin therapy or angioplasty.
2. Coumadin therapy -- continue to dose based on PT and the multiple of the control, i.e. 1.5, until steady state is reached. Patient instructions for Coumadin:
   1. Do not radically change your diet, i.e. routinely eating a large amount of foods high in vitamin K -- example spinach, cauliflower, rice or changing to strictly vegetarian diet will require a re-evaluation of Coumadin dosing to remain therapeutic.
   2. Do not take additional vitamins while taking the Genesis product line without checking with your health-care provider.

From a practical point, the most significant problem occurs when you stabilize the patient on Coumadin in the hospital and then they go home and take megadoses of vitamin E or vitamin K rich foods -- you may need to re-dose Coumadin.