How to Select tPA Therapy* Patients with Deep Vein Thrombosis for Wzyne D. Brown, M.D., MPH.; and Samuel Z. Goldhaber M.D., EC.C.P Despite proximal enthusiasm patients eligible deep Therefore, for venous for this we screened Hospital patients grams. ower extremity medical confronted. strategy deep vein thrombosis that most complications patients with LYSIS: 5 72 (83%) with venohad is a common physicians this have condition has DVT been Hospital, 22% for thrombolytic (1) recent trauma patients with therapy for 5-7 din) 1968 Brigham TRIALS I3 17 I I (nl6) -‘I .---- I I I KakKor, 1969 interest associated (n=20) DVr days, initiation Thus, of warfarin second hospital fibrin-specific in thrombolytic with DVT. has been is renewed the complications tients (Fig a morbidity heparin with acute proximal DVT in several individual studies have usually with certainty Goldhaber and colleagues’ pooled the results of 6 randomized vs heparin in venographically proved acute DVT. analysis showed that thrombolysis was achieved among by Cou- there compared size inadequate to determine and safety of SK. Therefore, (Coumaof recombi(rtPA), to decrease randomized alone and advent activator agent, therapy (SK) often were: thrombolytic one-filTh of our followed the had the heparin veins. eligible sodium day, for treating trials. However, a sample efficacy were major exclusion criteria (2) recent GI bleeding, for 3-6 months. With tissue-type plasminogen anticoagulation to calf limited DVr. on the therapy human DVT proximal bleeding disorder. given to approximately proximal therapy had with SK-treated patients (Fig 1). However, was 2.9 times the than rate higher trials of SK The pooled 3.7 times patients of major among given bleeding S K-treated pa- 2). ‘ 0- ) 15(17%) therapy. The or surgery, (3) history of a therapy could be more Robertson, and of patients Streptokinase Division. RATIO 9 DVT, Overall, second-generation IV heparin and Women’s proximal madin nant pulmonary hypertenThe standard method 6 RANDOMIZED RISK positive (DVT) 5Fmm the Cardiovascular Division, Brigham Harvard Medical School, Boston. Reprint requests: Dr Brown, Cardiovascular and Womens Hospital, Boston 02115 CLOT of is unknown. and Wmen in 1987. Of 240 practicing associated acute to treat proportion at Brigham include pulmonary embolism (PE), sion, and the postphlebitic syndrome. of treating the leg venography DVT, 87 (36%) had positive venograms, condition The therapeutic all patients who underwent with suspected Of those with therapy thrombolytic (DVT), using thrombosis MATERIAL I I I I -oi---- Robertson, 1970 (nI6) 9Th (n.04) #{149} I I I i -i- Tsopogos, AND METHODS To investigate the efficacy and safety of rtPA in acute DVT, we participated in a Genentech-sponsored study in which patients with . Table Porter, -o---. - Elliott 1975 Trauma ,1979 (n5l) A RRw (95%CL) 1-Exclusion Criteria (n50) 3.7(2.5.5.7) o < 0.0001 1. A risk ratio greater than 1 indicates a beneficial effect of SK for clot lysis. Overview of 6 randomized trials of SK vs heparmn for acute DVT indicates an overall 3.7 times superior lysis rate (solid, heavy vertical line) for SK vs heparin. The pooled risk ratio is statistically significant (p<0.001), with 95% confidence limits (hatched vertical lines) of 2.5-5.7. In each of the 6 individual trials, SK achieved superior lysis (open circles), but the lower 95% confidence limit (closed circle, left side of each solid horizontal line) was greater than 1, indicating statistical significance, in only 2 of the 6 individual trials. FIGURE 276S Downloaded From: http://publications.chestnet.org/ on 09/27/2014 or major surgery at a noncompressible site within preceding 14 days CI bleeding within Significant bleeding History of CVA Severe head Uncontrolled by several preceding diathesis or spinal trauma hypertension 4 wk or known within (diastolic bleeding past blood disorder 3 mo pressure >100 mm Hg measurements) Significant hepatic disease as evidenced by a prothrombin prolonged 3 over normal or bilirubmn level 3 mgfdl Patients with less than 100,000 platelets/cu mm Serum creatinine >5 mg/dl Lactating women and women known or thought to be pregnant Patients with known hypersensitivity to contrast material Tissue Plasminogen Activator In Cardiopulmonary time Disease MAJOR BLEEDING COMPLICATIONS: RISK Jo 0 2.0 3 RANDOMIZED TRIALS RATIO 3.0 4.0 I I Robertson, 5.0 6.0 T 1968 (nI6) Porter, 1975 (n50) Elliott, 1979 (n5I) A RRw (95%CL) 2.9(1.1, 2. A risk ratio greater 8.1) 0.04 p 1 indicates more major bleeding complications associated with SK than of SK vs heparin (3 of the trials in Figure 1 provided inadequate information on bleeding complications) for acute DVT indicates an overall 2.9 increase in the major bleeding rate (solid, heavy vertical line) for SK compared with heparin. The pooled risk ratio is statistically significant (p = 0.04), but the 95% confidence limits are wide, reflecting the small sample size among the individual trials. FIGURE with heparin. An than of 3 trials overview venographically proved DVT were randomized to 1 of 3 treatment groups: (1) rtPA alone, (2) heparin alone, or (3) the combination of rtPA plus heparin. Each patient underwent a follow-up venogram at 24 hs to evaluate clot lysis, the principal end point of the study. As a participating center, we were available around-the-clock to screen all patients undergoing venography. This screening process provided us with the opportunity to determine the proportion of patients thought to have DVT who were eligible to receive rtPA. The major DV1’ study inclusion criteria were: (1) venographically confirmed proximal DVT, (2) age range, 18-75 years, and (3) written informed consent. Phlebographic confirmation of thrombosis was required, with visualization of a filling defect proximal to the calf veins. (Lack thrombosis of filling was not The exclusion through DVT criteria October who of the deep adequate system due 14 women. had proximal Of those 61% DVT, to Harvard Community Brigham and Women Health Hospital), of DVT (Table 3). Overall, 22% of patients for thrombolytic patients were with Plan (an HMO affiliated with and 13% had a past history proximal eligible more than a history 1 contraindiof trauma or site within preceding 14 Ficuax 3. Contraindications to rtPA among 72 patients venographically proved proximal deep vein thrombosis. with CHEST/9515/MAV,1989/Supplement 277S surgery at a noncompressible had were had with of these patients were 28 (39%) 78% DVT 1 contraindi- Some There but for venography 30% belonged at least cation. cation. therapy, referred in-patients, the to extensive for eligibility.) are listed in Table 1. From we evaluated 240 patients 1987, underwent venous with who December, with 1986 suspected leg venography. RESULTS The venographic demonstrated DVT negative, and 87 6 (2%) of 240 (36%) (17%) Of the men was men under Table with and Mean Range 18-29 DVT, Of the (62%) 87 patients with proximal DVT, and (below the trifurcation). 15 DV1 for the mean 53 years (Table the age of 40 developed proximal DVT No. Men suspected 147 for women 2-Characteristics yr proximal with for indeterminate. 72 patients 47 years patients positive venograms, 72 (83%) had had DVT limited to calf veins positive Age, results of 72 Patients with No. Women 47 53 age 2). Three compared Proximal DVT Total 0 8 8 30-39 3 6 9 40-49 5 3 8 50-59 10 6 16 17 35 14 37 31 72 60 Total Downloaded From: http://publications.chestnet.org/ on 09/27/2014 Table 3-Characteristics of 72 Patients Harvard Proximal DVT declined 1. 28 J 22 50 DVT Community with In 1988, a positive we enrolled 18% venogram, an additional were eligible 72 to receive rtPA. Of the 72 patients with proximal DVT, 16 (22%) were eligible to receive rtPA. Thus, in our patient 72 population, patients 9 Health to participate. 8 patients. Of patients No. Feature In-patients Out-patients HCHP* Non-HCHP Past history with with rtPA can be given to approximately one-fifth DVT. These patients are at highest risk pulmonary embolism fore, implementation Plan. high-risk DVT and postphlebitic of a system that patients eligible for syndrome. screens and of for Thereidentifies thrombolytic therapy should be undertaken. days, weeks, 16(22%) who had 14 (19%) with diasthesis or a known CI bleeding within the preceding a history of a significant bleeding chronic bleeding them eligible (Fig 3). Of 16(22%) patients with proximal to receive rtPA, 12 were enrolled disorder that 4 made REFERENCE 1 Goldhaber analyses DVT who were in the protocol, 278S Downloaded From: http://publications.chestnet.org/ on 09/27/2014 eligible and 4 SZ, Buring of phlebographically Am J Med JE, Lipnick RJ, Hennekens CH. Pooled trials of streptokinase and heparin in randomized documented 1984; acute deep venous thrombosis. 76:383-87 Tissue Plasminogen Activator in Cardiopulmonary Disease