Warfarin prosthetic heart valves

All patients with a mechanical prosthetic heart valve should receive concomitant unfractionated heparin or a low molecular weight heparin in combination with warfarin pharmacotherapy until the INR is therapeutic and stable for two consecutive days... 

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. 

Dipyridamole (Persantine) is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves and, in combination with aspirin, reduces thrombosis in patients with thrombotic diseases. Dipyridamole by itself has little or no benefit in fact, in trials where a regimen of dipyridamole plus aspirin was compared with aspirin alone, dipyridamole provided no additional beneficial effect. Dipyridamole interferes with platelet function by increasing the cellular concentration of adenosine 3, 5 -monophosphate (cyclic AMP). This effect is mediated by inhibition of cyclic nucleotide phosphodiesterase and by blockade of uptake of adenosine, which acts at A2 receptors for adenosine to stimulate platelet adenylyl cyclase. The only current recommended use of dipyridamole is for primary prophylaxis of thromboemboli in patients with prosthetic heart valves the drug is given in combination with warfarin. 

A 71-year old woman, who was taking maintenance warfarin for a prosthetic heart valve, took a 5-day course of azithromycin, and 6 days later her INR rose from 2.5 to 3.5-15 (189). 

Dipyridamole (persantine) is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves. A single study suggests that dipyridamole plus aspirin reduces strokes in patients with prior strokes or transient ischemic attack. A formulation containing 200 mg of dipyridamole, in an extended-release form, and 25 mg of aspirin (aggrenox) is available. 

Dipyridamole is a pyrimidopyrimidine derivative with vasodilatory and antiplatelet properties (Fig. 31.17). Dipyridamole exerts its antiplatelet function by increasing cellular concentrations of cAMP via its inhibition of the degradating enzyme, cyclic nucleotide PDE3. It also blocks adenosine uptake, which acts at A2 adenosine receptors to stimulate platelet adenyl cyclase. Less common uses for this drug include inhibition of embolization from prosthetic heart valves when used in combination with warfarin (the only currently recommended use) and reduction of thrombosis in patients with thrombotic disease when used in combination with aspirin. Alone, dipyridamole has little, if any, benefit in the treatment of thrombotic conditions (102). 

Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement danger of aspirin compared with dipyridamole. Am J Cardiol (1983) 51, 1537-41. 

The preliminary report of a meta-analysis of these four studies, concluded that the combined use of oral anticoagulants and aspirin (100 mg to 1 g daily) significantly reduced mortality and embolic complications in patients with prosthetic heart valves, with an estimated increased odds ratio of major bleeds of 1.7 and of total bleeds of 1.98. Nevertheless the overall picture was that the benefits possibly outweighed the problems. In a more recent meta-analysis, which excluded one non-randomised study, but included 2 other randomised controlled studies, the risk of major bleeding for the combination of warfarin and aspirin was 1.53. For the two low-dose aspirin (100 mg daily) trials, there did not appear to be an excess risk of major bleeding. Another analysis of these studies provided essentially the same risk of increased major bleeding with the eombina-tion. ... 

In one early report, a patient with a prosthetic heart valve and stabilised on warfarin developed blood blisters and bruised easily 12 days after starting miconazole gel 250 g four times a day for a presumed fungal mouth... 

In a study in 6 healthy subjects, miconazole 125 mg daily for 18 days (in the form of tablets) caused a very marked fivefold increase in prothrombin time response to a single dose of warfarin given on day 3. In addition, there was a threefold inerease in the AUC of warfarin, with S-warfarin most affected (fourfold), and R-warfarin increased 1.7-fold. In one early case report with warfarin, one patient with a prosthetic heart valve and stabilised on warfarin was found to have a prothrombin time ratio of 23.4 within 10 days of starting miconazole tablets 250 mg four times a day for a suspected fungal diarrhoea. He developed two haematomas soon after both drugs were withdrawn, and was subsequently lestabilised, in the absence of miconazole, on his former dose of warfarin. ... 

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