Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo(®) ) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas.

Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing.

Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism.

BACKGROUND: Standard therapy to prevent recurrent venous thromboembolism includes 3 to 12 months of treatment with full-dose warfarin with a target international normalized ratio (INR) between 2.0 and 3.0. However, for long-term management, no therapeutic agent has shown an acceptable benefit-to-risk ratio. METHODS: Patients with idiopathic venous thromboembolism who had received full-dose anticoagulation therapy for a median of 6.5 months were randomly assigned to placebo or low-intensity warfarin (target INR, 1.5 to 2.0). Participants were followed for recurrent venous thromboembolism, major hemorrhage, and death. RESULTS: The trial was terminated early after 508 patients had undergone randomization and had been followed for up to 4.3 years (mean, 2.1). Of 253 patients assigned to placebo, 37 had recurrent venous thromboembolism (7.2 per 100 person-years), as compared with 14 of 255 patients assigned to low-intensity warfarin (2.6 per 100 person-years), a risk reduction of 64 percent (hazard ratio, 0.36 [95 percent confidence interval, 0.19 to 0.67]; P<0.001). Risk reductions were similar for all subgroups, including those with and those without inherited thrombophilia. Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin (P=0.25). Eight patients in the placebo group and four in the group assigned to low-intensity warfarin died (P=0.26). Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism, major hemorrhage, or death. According to per-protocol and as-treated analyses, the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent. CONCLUSIONS: Long-term, low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism.

Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period.

This study evaluated enoxaparin alone versus initial enoxaparin followed by warfarin in secondary prevention of venous thromboembolic events in adults with active malignancy. Cancer patients (n = 122) with acute symptomatic venous thromboembolic events were randomly allocated to receive subcutaneous enoxaparin 1.0 mg/kg every 12 hours for 5 days, followed by 1.0 mg/kg daily (group 1a) or 1.5 mg/kg daily (group 1b) for 175 days, or subcutaneous enoxaparin 1.0 mg/kg every 12 hours for at least 5 days and until a stable international normalized ratio of 2 to 3 was achieved on oral warfarin begun on day 2 and continued to day 180 (group 2). There were no significant differences in major and minor bleeding rates between treatment groups. No bleeding events were intracranial or fatal. Enoxaparin treatment was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of venous thromboembolic events in patients with active malignancy.

Fosinopril versus amlodipine comparative treatments study: a randomized trial to assess effects on plasminogen activator inhibitor-1.

BACKGROUND: ACE inhibitors and calcium antagonists may modulate fibrinolysis. We conducted a randomized controlled trial to assess the effects of these drugs on plasminogen activator inhibitor-1 (PAI-1) antigen, an inhibitor of fibrinolysis. METHODS AND RESULTS: Participants with hypertension and type 2 diabetes mellitus (n=96, 51% black) were randomized after an initial 4 weeks of placebo to double-blind 20 or 40 mg fosinopril or 5 or 10 mg amlodipine daily for 4 weeks in a fixed-dose regimen. After 4 weeks of placebo washout, the patients received 4 weeks of crossover treatments. After treatment with placebo, systolic and diastolic blood pressure were 143+/-2 and 86+/-1 mm Hg and plasma PAI-1 was 43.4+/-2.3 ng/mL. Amlodipine achieved a greater systolic and diastolic blood pressure reduction than fosinopril (10 mm Hg versus 8 mm Hg, P=0.029, and 5 mm Hg versus 3 mm Hg, P=0.040, respectively) but tended to increase PAI-1, whereas fosinopril tended to decrease PAI-1 (5.4+/-3.6 versus -3.8+/-2.5 ng/mL, P=0.045). The PAI-1 changes depended on drug dose (6.5+/-6.1 and 3.4+/-3.9 ng/mL with amlodipine 10 and 5 mg, respectively, and -0.4+/-3.1 and -7.4+/-4.0 ng/mL with fosinopril 20 and 40 mg, respectively, P for trend 0.024). No significant differences between fosinopril and amlodipine were found for short-term changes in tissue plasminogen activator antigen, fibrinogen, C-reactive protein, and interleukin-6. The findings were similar in black and white participants. CONCLUSIONS: Short-term treatment with fosinopril significantly reduced PAI-1 compared with amlodipine in a dose-dependent fashion. This effect, which was independent of blood pressure reduction, may account for the improved clinical outcomes achieved with ACE inhibitors compared with calcium antagonists.

Safety and efficacy of alteplase for restoring function in occluded central venous catheters: results of the cardiovascular thrombolytic to open occluded lines trial.

PURPOSE: To evaluate the safety and efficacy of alteplase (TPA) for restoring function to occluded central venous catheters (CVCs). PATIENTS AND METHODS: The study design was a phase III, open-label, single-arm multicenter trial. Subjects with occluded, nondialysis CVCs were enrolled. All subjects received a 2-mg dose of TPA within the dysfunctional catheter lumen that was allowed to dwell for 30 to 120 minutes. Functionality was tested at 30 and 120 minutes. If the CVC remained obstructed at 120 minutes, a second 2-mg TPA dose was allowed to dwell for 30 to 120 minutes. The primary safety end point was the rate of intracranial hemorrhage (ICH) within 5 days of treatment, and serious adverse events were recorded up to 30 days. RESULTS: Nine hundred ninety-five patients received treatment (female, 562; male, 433; mean age, 50.7 years; range, 2 to 91 years). CVCs treated were as follows: single (26%), double (39%), or triple (6%) lumen catheters or ports (29%). The primary end point was 0% ICH within 5 days. There were no cases of death, major bleeding episodes, or embolic events attributable to treatment. Flow was successfully restored in 52% and 78% of CVCs at 30 and 120 minutes after one dose, and 84% and 87% at 30 and 120 minutes after a second dose, respectively. Restoration of flow was 86%, 93%, 90%, and 79%, for single, double, and triple lumen catheters and ports, respectively. Estimated 30-day catheter patency was 74%. CONCLUSION: A regimen of up to two 2-mg doses of TPA is safe and effective for the restoration of flow to occluded central venous catheters.

Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia.

OBJECTIVE: To retrospectively assess the signs and symptoms indicative of adverse reactions to repeated exposures to lepirudin in patients with heparin-induced thrombocytopenia who received at least 2 courses of lepirudin therapy. PATIENTS AND METHODS: Medical records were retrospectively assessed from adult patients who received at least 2 courses of lepirudin therapy separated by at least 1 week between January 1999 and June 2002 at The Cleveland Clinic, Cleveland, Ohio. We evaluated the list of 289 low-level terms for possible signs and symptoms of anaphylactic reactions In the medical dictionary for regulatory activities as well as patient vital signs to detect manifestations of immediate hypersensitivity reactions. Vital signs from the day before initiation of lepirudin therapy were compared with those from days 1 and 2 after exposure. RESULTS: No cases of anaphylaxis or allergic reaction related to lepirudin administration were identified among 43 adult patients. On day 1 of lepirudin, 10 patients had lower systolic blood pressures (by > or =20 mm Hg) than pre-lepirudin values, and 4 patients had systolic blood pressures of less than 100 mm Hg. CONCLUSIONS: Isolated asymptomatic decreases in blood pressure after patient reexposure to lepirudin most likely do not reflect anaphylaxis due to lepirudin. We believe that isolated and uncommon cases of anaphylaxis temporally related to lepirudin exposure should not preclude its use in patients with heparin-induced thrombocytopenia and past lepirudin exposure.

Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review.

Venous thromboembolic events (VTEs) represent a serious complication related to hormonal contraception and hormone replacement therapy (HRT). Evidence on hormonal contraceptive- and HRT-related VTEs is derived almost exclusively from observational studies and points to a 2- to 6-fold increased relative risk of VTEs with either therapy. Oral contraceptive pills that contain third-generation progestins (desogestrel or gestodene) seem to be associated with greater VTE risk than those that contain levonorgestrel. Oral contraceptive pill use and HRT are associated with exponentially higher VTE relative risks when used by women who carry an inherited hypercoagulable state. The indication of a lower or a lack of VTE risk associated with the use of progestin-only contraceptives and with transdermal HRT suggests that these therapies may be safer than combination oral contraceptive pills and oral HRT for women in whom oral estrogen therapy is considered contraindicated. Data that support such safety advantages are limited and should be interpreted with caution.

Incidence and risk factors of venous thromboembolism (VTD) in patients with amyloidosis.

BACKGROUND: Coagulation problems in amyloidosis are historically associated with bleeding tendencies (mostly Factor X abnormalities). Increased clotting was observed in isolated cases diagnosed with low-grade disseminated intravascular coagulation (DIC). Problem of venous thromboembolic disaease (VTD) in amyloidosis was not systematically investigated. METHODS: We evaluated frequency of VTD and risk factors for VTD in 56 consecutive amyloidosis patients with a documented disease evaluated and followed up at our Center from 1991-2001. Data was collected in 5 categories: (a) demographics, (b) disease and treatment, (c) thrombosis case information, (d) major risk factors for thrombosis and (e) baseline laboratory data. Univariable correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: Mean age of the patients was 67 (years range 21-83). Male/female percentage ratio was 70/30. 29% of the patients had high creatinine level (> 1.4 mg/dl). Personal or family history of VTD was recorded in 2 and 0% of patients, respectively. Known hypercoagulable state was present in 1 patient (2%). 8% of patients were smokers. Of 56 patients, 6 developed VTD (11%). Median time from diagnosis of amyloidosis to VTD was 12.5 month (range 1-107). Treatment was given within a median of 1 month (range 0-4) from the development of thrombosis. Only sites of VTD were lower extremities. No cases were associated with I.V. line. 1 case (17%) was identified postoperatively. We identified several univariable correlates of VTD in amyloid patients, including greater age at diagnosis (HR-2.99, P = .041), personal history of DVT (HR-47.7, P = .006) and immobility (HR-11.78, P = .006). Presence of circulating serum M-protein had protective role in our analysis (HR-.08, P = .031). There was no correlation with the type of treatment patients were receiving. CONCLUSION: Risk for thromboembolic diseases in patients with amyloidosis is similar to one previously described for multiple myeloma. Additional studies with higher number of thromboembolic events could help to further elucidate risk factors for VTD in this population of patients.

Recombinant urokinase for restoration of patency in occluded central venous access devices. A double-blind, placebo-controlled trial.

The interval occlusion of central venous access devices (CVADs) remains a significant clinical problem, often requiring re-intervention for catheter exchange or replacement. The purpose of this Phase 3, multi-center, double-blinded study was to test the hypothesis that instillation of recombinant urokinase (r-UK) 5000 IU/ml is superior to placebo in restoring total catheter patency to an unselected cohort of occluded CVADs. After obtaining informed consent, adult and pediatric patients with occluded, non-hemodialysis CVADs of any duration or type were randomized (2 : 1) to receive either r-UK 5000 IU/ml or placebo instilled into all occluded lumens of their catheter. Catheter function was assessed at 5, 15 and 30 min after the first instillation. If the catheter remained occluded after 30 min, a second dose was instilled with repeat assessments at 5, 15 and 30 min. The primary efficacy variable was the restoration of catheter function to all treated lumens (i.e., total catheter patency) after one or two instillations. Catheters that were not successfully recanalized after two instillations were allowed to receive up to two instillations of open-label r-UK administered in the same manner. The primary safety variable was the occurrence of hemorrhagic and non-hemorrhagic events within 72 hr after instillation. A total of 180 patients were enrolled at 43 sites in the United States and Canada. Most patients were adults, although 20% were

Pharmacologic and clinical characteristics of thrombolytic agents.

Arterial and venous thromboembolic events, including myocardial infarction, ischemic stroke, peripheral arterial thrombosis, deep venous thrombosis, and pulmonary embolism are common potentially life-, organ-, and limb-threatening vascular diseases. Anticoagulant therapy is recommended in these settings to prevent further thrombosis pending gradual clearance of the thrombotic occlusion by the endogenous fibrinolytic system. Recognition of the importance of the fibrinolytic system in thrombus resolution has resulted in the development of pharmacologic fibrinolytic (thrombolytic) agents to facilitate rapid restoration of vascular patency. Several plasminogen activator (PA) thrombolytic agents with different pharmacokinetic and pharmacodynamic properties have been developed to treat thrombotic disease. Newer PAs have been developed as "fibrin-specific", bolus-administration drugs to primarily treat acute coronary syndromes. Continuous infusions of these fibrin-specific PAs have become popular for the lysis relatively larger peripheral vascular thromboses. Loss infusion of newer tissue-type plasminogen activator-based PAs may result in an increased risk of bleeding, including intracranial hemorrhage. Currently available data fail to provide compelling evidence that newer PAs offer significantly greater efficacy and safety than well-established agents like urokinase when used to treat peripheral vascular thrombosis.

Detection of a novel point mutation of the prothrombin gene at position 20209.

Detection of the prothrombin G20210A mutation was performed on the LightCycler Instrument (Roche Molecular Biochemicals, Mannheim, Germany) using commercially available primers and hybridization probes. Herein we report four cases from unrelated African American individuals where LightCycler analysis showed atypical melting curves. Sequence analysis of the four samples showed heterozygosity for a C to T mutation 1 bp upstream from the known 20210 mutation at position 20209. The clinical significance of this mutation is not known, but three patients in whom it was detected had a history of venous thrombosis or stroke. The fourth patient had severe liver disease, which may have masked thrombotic predisposition. Since most assays used to detect the G20210A mutation use a PCR/restriction digestion assay, which would not detect the C20209T mutation, this new mutation may be underrecognized when prothrombin gene mutation testing is performed by PCR/restriction digestion assay.

Calf deep venous thrombosis should be treated with anticoagulation.

A 50-year-old man with hypertension presents with a 2-day history of right calf swelling and pain. Venous duplex ultrasound reveals a right soleal vein thrombosis. He denies history of bleeding, renal disease, and symptoms suggestive of pulmonary embolism (PE). Physical examination is unrevealing except for calf tenderness, redness, warmth, and swelling. He is ambulatory. A decision is made to treat the calf deep venous thrombosis (DVT) with anticoagulation.

Patients with inferior vena caval filters should receive chronic thromboprophylaxis.

A 32-year-old man with testicular carcinoma is diagnosed with an acute left leg deep venous thrombosis (DVT) during his fourth cycle of combination chemotherapy. Because of anticipated moderate to severe thrombocytopenia, anticoagulation is initially avoided and an inferior vena cava (IVC) filter is placed to prevent pulmonary embolism (PE). After completion of all chemotherapy he is deemed to be in remission and anticoagulation is begun. The optimal duration of anticoagulation in this patient is pondered.

Estrogen-containing oral contraceptives are allowable in young women with factor V Leiden heterozygosity without a history of thrombosis.

An 18-year-old woman without significant past medical and surgical history presents to discuss the safety and efficacy of oral contraceptives. She is sexually active and currently relying on condoms alone for birth control. Her cousin had a deep venous thrombosis (DVT) following a pregnancy. As part of the family screening, this patient was identified as a factor V Leiden heterozygote. The risks and benefits of initiating oral contraceptives are discussed.

Diagnosis of venous thromboembolic disease in cancer patients.

Venous thromboembolic disease is a common but likely underdiagnosed condition in the cancer patient population. Timely and accurate diagnosis of venous thromboembolism is imperative due to the unacceptable morbidity and mortality associated with a misdiagnosis. Because diagnosis of the condition based on clinical grounds alone is unreliable, physicians should select an appropriate objective diagnostic test to confirm or refute their clinical impressions. Compression duplex ultrasound is the best initial imaging test for both suspected upper- and lower-extremity deep venous thrombosis. Magnetic resonance venography (MRV) is a valid alternative when ultrasound is inconclusive, but contrast venography remains the "gold standard." Suspected pulmonary embolism should be initially evaluated by helical (spiral) computed tomography (CT) or ventilation/perfusion lung scintigraphy, the former being preferred in cases of obvious pulmonary or pleural disease. Indeterminate studies should prompt performance of contrast pulmonary angiography. Inferior vena cava thrombosis is also best assessed by contrast venography, with MRV and CT reserved as alternative imaging modalities. Evidence to date suggests that D-dimer assays remain unreliable in excluding venous thromboembolism in cancer patients. A newer latex agglutination D-dimer assay may prove to be clinically useful in this setting.

Clinical utility of subcutaneous hirudins.

The clinical utility of subcutaneous hirudins is discussed. The term "hirudins" refers to a class of antithrombotic agents structurally derived from the medicinal leech salivary protein hirudin. Breakthroughs in biotechnology over the past 20 years have resulted in the development of recombinant versions of hirudin (r-hirudin). Lepirudin is one such r-hirudin that is identical to natural hirudin except for the substitution of leucine for isoleucine at the N-terminus and the elimination of a sulfate group on the tyrosine at position 63. Another r-hirudin, desirudin, is identical to hirudin except for a valine-valine in the N-terminus and the absence of the sulfate group on tyrosine at position 63. Both r-hirudins are bivalent and tightly bind to both the catalytic site and the exposite of thrombin to exert their inhibitory effects on thrombin. Unfractionated heparin (UF) and low-molecular-weight heparins (LMWHs) are widely used in medical and surgical patients to prevent and treat arterial and venous thrombotic events. Besides bleeding, the major adverse effect of heparins is heparin-induced thrombocytopenia (HIT). HIT is associated with a paradoxical hypercoagulable state and marked risk of clinical thrombosis. Management of HIT requires the immediate cessation of all heparin exposure, and the initiation of an alternative anticoagulant. Because r-hirudins are effective agents and do not cross-react with HIT-associated antibodies, they are excellent anticoagulants in patients with past or current HIT. Clinical trials have also demonstrated the efficacy and safety of subcutaneous (s.c.) r-hirudins compared to heparins in non-HIT settings. Results of these trials support the use of r-hirudin therapy in patients with HIT or at risk of developing HIT. Additionally, case reports have described safe and effective use of s.c. r-hirudin therapy in the outpatient setting in both HIT and non-HIT patients.

Simultaneous deep venous thrombosis and acquired factor VIII inhibitor.

Acquired hemophilia A is a life-threatening immune-mediated hemorrhagic disorder that is most often found in individuals older than 50 who present with an unexplained activated partial thromboplastin time (aPTT) prolongation and clinically significant bleeding. The prolonged aPTT associated with acquired hemophilia A reflects factor VIII activity deficiency due to neutralizing or clearing autoantibodies. Deep venous thrombosis, in contrast, is a veno-occlusive disorder associated with several distinct hypercoagulable states that can result in significant morbidity and mortality due to pulmonary embolism, thrombus extension, and the post-thrombotic syndrome. A prolonged aPTT in the setting of thrombosis may reflect the presence of a lupus anticoagulant. In the absence of accurate diagnosis and the immediate institution of specific therapy, both disorders can be fatal. Three cases of acquired factor VIII inhibitors that included a prolonged aPTT, bleeding, and duplex ultrasound evidence of deep venous thrombosis are presented. The diagnostic and therapeutic challenges posed by these cases as well as a proposed mechanism by which pathologic thrombosis can develop in a patient with a life-threatening bleeding disorder are discussed.

Goal-oriented thrombolytic therapy for venous thromboembolic disease.

The goal of a therapeutic intervention should be to positively impact a meaningful patient outcome. Too often, though, efficacy of a treatment is based on a surrogate endpoint. Thrombolytic therapy for venous thromboembolic disease is an example of a treatment whose success is primarily based on radiographic or echocardiographic endpoints and not endpoints such as symptom relief, functional capacity, quality of life, thrombosis recurrence, and survival. Thrombolysis for lower-extremity deep venous thrombosis does not reduce the incidence of pulmonary embolism, has unclear impact on the rates of post-thrombotic syndrome, and is associated with increased rates of major hemorrhage compared to conventional anticoagulation. Reserving thrombolysis for limb-threatening thrombosis especially in the young seems prudent. Currently available evidence does not support the routine use of thrombolytic therapy in patients with hemodynamically stable pulmonary embolism regardless of right ventricular function status. Risks, benefits, and alternative therapies must always be considered, and therapy must be guided by individual case circumstances and the best available scientific evidence.

Advances in diagnosing and excluding pulmonary embolism: spiral CT and D-dimer measurement.

No single imaging study or blood test is 100% sensitive and specific for pulmonary embolism. A combination of pretest clinical probability assessment, noninvasive pulmonary imaging (V/Q scanning or spiral CT), and D-dimer testing seems prudent before pursuing pulmonary angiography.

Phase II study of vincristine sulfate liposome injection (Marqibo) and rituximab for patients with relapsed and refractory diffuse large B-Cell lymphoma or mantle cell lymphoma in need of palliative therapy.

BACKGROUND: VSLI (Marqibo) is active in advanced non-Hodgkin lymphoma (NHL) and untreated aggressive NHL. Because of its favorable hematologic toxicity profile, VSLI might be useful in patients unable to tolerate myelosuppressive therapies. PATIENTS AND METHODS: Twenty-two patients with heavily pretreated, advanced CD20(+) DLBCL or MCL were treated with VSLI 2.0 mg/m(2), without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m(2). ORR, complete response (CR), or partial response (PR), was the primary end point. Secondary end points included response duration, time to progression (TTP), and OS. Safety variables included adverse events and neurologic assessments. RESULTS: The ORR was 13 of 22 (59%); 6 patients achieved a CR (27%), and 7 patients achieved a PR (32%). Median response duration, TTP, and OS were 147 days, 121 days, and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. Grade 3 peripheral neuropathy, febrile neutropenia, and constipation were reported in 4, 2, and 1 patients, respectively. CONCLUSION: VSLI plus rituximab resulted in durable responses in patients with heavily pretreated advanced stage DLBCL and MCL. The toxicity profile was predictable and manageable with limited hematologic toxicity. Despite near-universal previous VCR exposure (96%) and doses of VSLI unachievable with standard VCR treatment, peripheral neuropathy and constipation were modest. This study supports further evaluation of VSLI as a component of DLBCL management.