низкомолекулярные гепарины в онкологии

[Dr.Vad]

На днях появились 2 близнецовые публикации, что назначение низкомолекулярного гепарина у пациентов с опухолями (с тромбозом или без) увеличивает их продолжительность жизни; наибольший положительный эффект от НМГ у пациентов с лучшим прогнозом и отсутствием метастатической диссеминации:

J Clin Oncol. 2005 Feb 7;

Randomized Comparison of Low Molecular Weight Heparin and Coumarin Derivatives on the Survival of Patients With Cancer and Venous Thromboembolism.

Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN.

PURPOSE: Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism. PATIENTS AND METHODS: Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups. RESULTS: During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02). CONCLUSION: The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.

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The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy.

Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR.

PURPOSE: Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS: Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS: In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION: A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

[Dr.Vad]

Опухоли повышают риск тромбоза в 7-12 раз:

Cancer Raises Blood Clot Risk by Sevenfold

Cancer greatly increases the risk that the patients will develop a blood clot in a vein (venous thrombosis), especially in recently diagnosed patients, patients with cancer that has spread to distant sites (metastases), and those with certain genetic mutations, according to Dutch researchers. While anticoagulant therapy might be beneficial, they say, the associated increased risk of bleeding has to be considered.

The findings, reported in the Journal of the American Medical Association, are based on a survey of 3220 consecutive patients who were diagnosed with a blood clot in the leg or lung between 1999 and 2002 at six clinics in the Netherlands. The group of 2131 partners of the patients was used as a comparison.

Cancer increased the risk of venous thrombosis 6.7-fold, Dr. Frits R. Rosendaal and colleagues, from Leiden University Medical Center, note. Patients with cancers of the blood system had the highest increased risk -- 28.0-fold -- followed by patients with lung cancer and GI cancer.

The highest risk of clots occurred within 3 months of the cancer diagnosis. At this point, cancer patients were 58.2-times more likely to develop venous thrombosis than were controls.

The presence of distant metastases raised the risk of thrombosis, over and above that seen with cancer alone, by 19.8-fold.

Furthermore, cancer patients who were also carriers of the factor V Leiden mutation or the prothrombin 20210A mutation were 12-times more likely to develop a clot than healthy non-carrier patients.

The author suggest that future studies address the issue of giving preventive anticoagulant therapy to patients with cancer in the first months after the diagnosis and to patients with distant metastases. "However, since these patients also have an increased risk of hemorrhage, this needs to be cautiously evaluated."

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Malignancies, Prothrombotic Mutations, and the Risk of Venous Thrombosis
Jeanet W. Blom, MD; Carine J. M. Doggen, PhD; Susanne Osanto, MD, PhD; Frits R. Rosendaal, MD, PhD

JAMA. 2005;293:715-722.

Context
Venous thrombosis is a common complication in patients with cancer, leading to additional morbidity and compromising quality of life.

Objective
To identify individuals with cancer with an increased thrombotic risk, evaluating different tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations.

Design, Setting, and Patients
A large population-based, case-control (Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3220 consecutive patients aged 18 to 70 years, with a first deep venous thrombosis of the leg or pulmonary embolism, between March 1, 1999, and May 31, 2002, at 6 anticoagulation clinics in the Netherlands, and separate 2131 control participants (partners of the patients) reported via a questionnaire on acquired risk factors for venous thrombosis. Three months after discontinuation of the anticoagulant therapy, all patients and controls were interviewed, a blood sample was taken, and DNA was isolated to ascertain the factor V Leiden and prothrombin 20210A mutations.

Main Outcome Measure Risk of venous thrombosis.

Results
The overall risk of venous thrombosis was increased 7-fold in patients with a malignancy (odds ratio [OR], 6.7; 95% confidence interval [CI], 5.2-8.6) vs persons without malignancy. Patients with hematological malignancies had the highest risk of venous thrombosis, adjusted for age and sex (adjusted OR, 28.0; 95% CI, 4.0-199.7), followed by lung cancer and gastrointestinal cancer. The risk of venous thrombosis was highest in the first few months after the diagnosis of malignancy (adjusted OR, 53.5; 95% CI, 8.6-334.3). Patients with cancer with distant metastases had a higher risk vs patients without distant metastases (adjusted OR, 19.8; 95% CI, 2.6-149.1). Carriers of the factor V Leiden mutation who also had cancer had a 12-fold increased risk vs individuals without cancer and factor V Leiden (adjusted OR, 12.1; 95% CI, 1.6-88.1). Similar results were indirectly calculated for the prothrombin 20210A mutation in patients with cancer.

Conclusions
Patients with cancer have a highly increased risk of venous thrombosis especially in the first few months after diagnosis and in the presence of distant metastases. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to have an even higher risk.

[Gilarov]

И в BMJ последнем такая же статья.

[Dr.Vad]

Что-то не заметил: нельзя ли точную ссылку?

[Dr.Vad]

Известно, что онкологические больные в еще большей степени, по сравнению с пациентами без онкологических заболеваний, подвержены риску развития тромбоза глубоких вен (ТГВ), часто приводящему к смертельно опасному исходу. Фрагмин (далтепарин натрия) известен как препарат, эффективно препятствующий развитию ТГВ и, как следствие, тромбоэмболии легочной артерии (ТЭЛА).

По словам профессора медицины из Университета Дж. Вашингтона д-ра Фреда Риклза, «тромбоз глубоких вен и тромбоэмболия легочной артерии очень опасны для онкологических больных и являются одной из самых распространенных причин смерти таких пациентов».

Результаты двойного слепого плацебо контролируемого исследования «FAMOUS», посвященного изучению эффективности и безопасности длительного применения Фрагмина у онкологических больных без тромбоза в анамнезе, с участием 385 пациентов с распространенным раком, продемонстрировали, что в группе пациентов, принимающих Фрагмин, улучшились показатели выживаемости.

Процент выживаемости через 2 и 3 года от начала лечения составлял в группе, принимавшей Фрагмин, соответственно, 78 процентов и 60 процентов, в сравнении с группой, получавшей плацебо, показатели в которой равнялись 55 процентов и 36 процентов.

Исследование FAMOUS было своего рода сенсационным, так как на фоне подобных исследований в этой области в нем впервые было выявлено улучшение выживаемости у онкологических пациентов, получавших лечение низкомолекулярным гепарином.

Показанные результаты демонстрируют реальные преимущества Фрагмина при длительном лечении онкологических больных и открывают перспективу дальнейших исследований этого направления.

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1. Kakkar et al. Journal of clinical oncology 2004; 22 (10): 1944 - 1948

[dr_medvedev]

Клексан и фраксипарин имеют лучшее соотношение анти Xa: анти II активности и показали преимущества перед дальтепарином в некоторых кардиологических исследованиях. Было бы интересно увидеть исследования по сравнению эффективности разных НМГ.