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.

______________________

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.

[Dr.Vad]

Уважаемый доктор Медведев,

По правде говоря, несмотря на различия между НМГ, преподносимые фарм-фирмами, и мнения экспертов, что НМГ клинически не взаимозаменяемые, но все гепарины включая и обычный будут работать одинаково, если их назнажать в экви-дозах (по поддержанию одинакового терапевтич. уровня анти-Ха) и в одинаковом временном режиме.

Вот пример некорректного сравнения, показывающий, что клексан 100 МЕ/кг дважды лучше, чем 175 Ме/кг тинзапарин 1 раз в сутки:

Michalis LK, Katsouras CS, Papamichael N, Adamides K, Naka KK, Goudevenos J, Sideris DA. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial.
Am Heart J. 2003 Aug;146(2):304-10

Это также подтвердилось и при применении фондапаринукса (исследования MATISSE) эквивалентная суппрессия фактора Ха в крови дает один. клин. эффект.
Последней каплей, на мой взгляд, было исследование, показавшее, что назначение обычн. гепарина с учетом массы тела (но не АЧТВ) было одинаково эффективным в лечении вем. тромбоза как и НМГ, назначенным тоже с учетом массы тела.

Тезисы были представлены на прошлой конференции ASH-2004, а полного текста статьи пока не видно в периодике.

[dr_medvedev]

В понятие эффективность входит и безопасность, удобство, compliance etc. Различия достигаются видимо за счет нескольких составляющих.

Гепарином можно добиться великолепных эффектов, в том числе и побочных. С другой стороны, некоторые ангиохирурги предпочитают гепарина сульфат в связи с более коротким периодом полувыведения.

[Dr.Vad]

Еще 2 мета-анализа появились почти одновременно, показывающие преимущества НМГ в продлении жизни у онкологических больных:

Cancer. 2007 Jul 17;
A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment : impact on survival and bleeding complications.
Kuderer NM, Khorana AA, Lyman GH, Francis CW.
James P. Wilmot Cancer Center and the Department of Medicine, University of Rochester, Rochester, New York.
BACKGROUND.: Preclinical evidence suggests that anticoagulants, in particular the low-molecular-weight heparins (LMWH), exert an antitumor effect, whereas clinical trials have reported conflicting results. The authors conducted a comprehensive, systematic review and meta-analysis of the evidence from randomized controlled trials (RCTs), to evaluate the impact of anticoagulants on survival and safety in cancer patients without venous thromboembolism. METHODS.: A comprehensive systematic literature review of RCTs was performed without language restrictions through May 2006 with subsequent updates to the end of 2006, including an exhaustive search of electronic databases, major conference proceedings, article references, and content experts. Two reviewers extracted data independently. Primary study outcomes were 1-year overall mortality and all bleeding complications. Major and fatal bleeding complications were secondary outcomes. RESULTS.: Across all 11 studies that were identified, anticoagulation significantly decreased 1-year overall mortality with a relative risk (RR) of 0.905 (95% confidence interval [95% CI], 0.847-0.967; P = .003). The RR for mortality was 0.877 (95% CI, 0.789-0.975; P = .015) for LMWH, compared with an RR of 0.942 (95% CI, 0.854-1.040; P = .239) for warfarin, resulting in an absolute risk difference (ARD) of 8% for LMWH and an ARD of 3% for warfarin. Improved survival with anticoagulation may be dependent on tumor type. Major bleeding episodes occurred less frequently in patients who received LMWH (ARD, 1%) compared with patients who received warfarin (ARD, 11.5%; P < .0001). Overall, fatal bleeding occurred rarely (ARD, 0.32%; P = .542). CONCLUSIONS.: Anticoagulants, particularly LMWH, significantly improved overall survival in cancer patients without venous thrombosis while increasing the risk for bleeding complications. However, given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results.
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Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006652.
Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.
Akl E, van Doormaal F, Barba M, Kamath G, Kim S, Kuipers S, Middeldorp S, Yosuico V, Dickinson H, Schünemann H.
BACKGROUND: Basic research and clinical studies have generated the hypothesis that anticoagulation may improve survival in patients with cancer through an antitumour effect in addition to the antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of heparin (including unfractionated heparin (UFH) and low molecular weight heparin (LMWH)) and fondaparinux to improve survival of patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including (1) A January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science; (2) Hand search of the American Society of Clinical Oncology and of the American Society of Hematology; (3) Checking of references of included studies; and (4) Use of "related article" feature in PubMed. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in cancer patients without clinical evidence of venous thromboembolism comparing UFH, LMWH or fondaparinux to no intervention or placebo and RCTs comparing two of the three agents of interest. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding. MAIN RESULTS: Of 3986 identified citations five RCTs fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin ( either UFH or LMWH). The overall methodological quality of the included studies was acceptable. Overall, heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95% CI: 0.65 to 0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95% CI: 0.38 to 0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95% CI: 0.60 to 1.06) or patients with advanced cancer (HR = 0.84; 95%: 0.68 to 1.03). The increased risk of bleeding with heparin was not statistically significant (RR = 1.78; 95% CI: 0.73 to 4.38). AUTHORS' CONCLUSIONS: Heparin has a survival benefit in cancer patients in general, and in patients with limited small cell lung cancer in particular. Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy. Future research should investigate the survival benefit of different types of anticoagulants (in different dosing, schedules and duration of therapy) in patients with different types and stages of cancers.

[Dr.Vad]

Thromb Haemost. 2007 Aug;98(2):434-9.
Effect of low-molecular-weight heparin on survival in patients with advanced pancreatic adenocarcinoma.
von Delius S, Ayvaz M, Wagenpfeil S, Eckel F, Schmid RM, Lersch C.
2nd Medical Department, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
This retrospective analysis aimed to identify whether low-molecular-weight heparins (LMWH) might improve survival in patients receiving chemotherapeutic treatment for advanced pancreatic adenocarcinoma. Two hundred forty-three patients who had received chemotherapy for advanced pancreatic adenocarcinoma were identified from a prospectively maintained database. Of these, 30 patients had to be excluded from analysis due to insufficient documentation. Of the remaining 213 patients 94 patients had been treated with LMWH, whereas 119 patients served as controls. Outcome was assessed in relation to overall survival, which was calculated from the date of initiation of chemotherapy to the date of death. There was no significant difference (hazard ratio, 0.8; 95% confidence interval (CI), 0.6 to 1.1; P = 0,2) between the two groups in terms of overall survival. The median survival was 7.1 months (95% CI, 5.8-8.4 months) in the LMWH group and 5.9 months (95% CI, 5.1-6.7 months) in the non-LMWH group. A positive effect of LMWH was seen in patients with metastatic disease (hazard ratio for LMWH vs. non-LMWH, 0,6; 95% CI, 0,4 to 0,8; P = 0,006) in contrast to those without metastatic disease (hazard ratio for LMWH vs. non-LMWH, 1; 95% CI, 0.6 to 1.7; P = 0,96). The median survival of patients with metastatic disease was 6,6 months (95% CI, 5-8, 2 months) and 3.8 months (95% CI, 2.5-5.1 months) for the LMWH group and the non-LMWH group, respectively. In conclusion, we found for metastatic pancreatic adenocarcinoma a survival advantage for patients receiving LMWH. Nevertheless, our observations need confirmation by prospective randomized studies.

[Dr.]

А что насчет обычного гепарина в профилактической дозе? (без контроля АЧТВ?)

[Dr.Vad]

Похоже, что обычный гепарин не столь антиканцерогенен, как НМГ: первые результаты были получены при их прямом сравнении при лечении ТГВ/ТЭЛА (данные мета-анализа):

The most recent one included nine
studies and over 3500 patients with VTE, 629 with
cancer.25 Patients were randomized to receive either
subcutaneous LMWH or intravenous UFH for 5 to 10
days, followed by oral anticoagulants for at least 3
months. In patients without cancer, there were no
differences in 3-month mortality between patients
treated with LMWH (39/1481) or UFH (41/1471).
However, 117 out of 629 cancer patients died within
the first 3 months of follow-up (46/306 in the LMWH
group and 71/323 in the UFH group). The pooled
odds ratio for the 3-month mortality in cancer
patients was 0.61 (95%CI 0.40 – 0.93) in favor of
LMWH. Differences in 3-month mortality between
the two groups remained after adjusting for some
prognostic factors (age, gender, tumor characteristics),
supporting the conclusion that the treatment
had a real effect. Again, the differences observed
could not be attributed to a higher incidence of fatal
bleeding or thrombotic complications in the UFH
group, which were equally infrequent in the overall
population (1.1% versus 1.3%).

[Ссылки доступны только зарегистрированным пользователям ]

Да и в эксперименте обычный гепарин оказывал меньшее влияние на онкогенез, поэтому его больше не исследовали на эту тему.