Treatment of Deep Venous Thrombosis

There is now abundant evidence that use of low molecular weight heparin (LMWH) for therapy in DVT/PE treatment is both safer and more effective than use of standard heparin. Evidence is also clear that stable patients with DVT/PE can be treated at home with LMW heparin. There are two low molecular weight hep-arins (LMW heparin) approved for therapy, enoxaparin 1mg/kg every 12 hours or tinzaparin 175 units/kg every day. For patients with low thrombotic burden one may use enoxaparin 1.5 mg/kg every day. For short courses of therapy most patients

do not need to have LMW heparin levels drawn. Patients who are very obese (greater than two times ideal body weight), pregnant, those with severe liver or heart failure, or those on long-term heparin therapy should have levels performed. In patients with renal failure dosing should be once per day. Levels are drawn four hours after injection and the therapeutic range for enoxaparin is 0.7-1.2 anti-Xa units.

These regimens may be used with either inpatients or outpatients. Although LMW heparin is more expensive than standard heparin, inpatient savings can be realized since multiple aPTT's or platelet counts are unnecessary. In addition, in inpatient populations the early trials demonstrated that LMW heparin was more effective and safe than standard heparin.

The ability to give LMW heparin subcutaneously has opened the door to outpatient therapy. Careful patient selection is crucial. A patient should be considered for outpatient therapy if the only thing that would lead to their admission was administration of intravenous heparin. The first dose of LMW heparin is given as soon as possible, and warfarin is started the first evening of diagnosis. The second dose of LMWH should be a "transition" to get the patient on an 8 am & 8 pm schedule. This is derived by adjusting the second dose of LMW heparin for the difference between the first and second dose. This is done by multiplying the patient's usual dose of 1mg/kg by the difference in time between the first two doses divided by 12. For example, if a 60 kg patient received his first dose at midnight, at 8 am the patient would get 40 mg and from then on 60 mg every 12 hours. Patients should be followed every day with a visit or phone check. One still needs to overlap LMW heparin and warfarin by 24 hours once the INR is in the therapeutic range.

As discussed in more detail in Chapter 22, standard heparin is fading from use due to its unfavorable pharmacokinetics and the demonstration of better outcomes with LMWH. If used, the absolute key in standard heparin use is to give enough. The standard bolus should be 5,000 units (10,000 for larger thrombi or pulmonary embolism). The initial drip should be 1400 units/hr. The aPTT should be checked 6 hours after the bolus and the drip adjusted accordingly. A supratherapeutic aPTT may just reflect the bolus. The drip should never be turned down until two consecutive aPTT's are supratherapeutic. Therapeutic range varies with different aPTT reagents and must be standardized at each laboratory with heparin levels. One must be very aggressive in rapidly achieving the proper aPTT.

All patients should receive at least five days of heparin therapy. Some authorities recommend that ten days of heparin should be given for large PE since it has not been proven that five days is sufficient therapy.

Warfarin is started the evening of diagnosis (or day five of therapy if ten days of heparin is being used) with a loading dose of 2.5-10 mg orally. Five mg is recommended in most patients. Young (under age 60) healthy patients may need a 10 mg loading dose while the frail elderly (over age 85) should start with 2.5 mg. Warfarin is titrated to an INR of 2-3. Use of warfarin affects all the vitamin K dependent proteins. Factor VII falls first, resulting in prolongation of the INR. However, the full antithrombotic effect of warfarin does not occur until factors X and II have fallen. This fall will take an additional 24 to 48 hours after factor VII levels fall. This is why patients should overlap heparin and warfarin therapy for several days.

Recently, it has been reported that the direct thrombin inhibitor ximelagatran in the dose of 36 mg twice a day can be used instead of heparin/warfarin in therapy of DVT/PE. Ximelagatran offers the advantage of more predicable dosing and lack of drug interactions. This agent is described in more detail in Chapter 23.

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