[Dr.Vad]

Любопытная работа опубликована в текущем журнале:

Am J Gastroenterol. 2007 Mar;102(3):507-15.
Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants.
Lanas A; on behalf of the Investigators of the Asociacion Espanola de Gastroenterologia (AEG).
Servicio de Aparato Digestivo, Hospital Clinico Zaragoza, Ciber Hepad, Zaragoza, Spain.

OBJECTIVES: After the withdrawal of some cyclooxygenase-2 (COX-2) selective inhibitors, traditional nonsteroidal anti-inflammatory drug (NSAID) use has increased, but without additional prevention strategies against upper gastrointestinal (GI) complications in many cases. Here, we report the effect of antisecretory drugs and nitrates on the risk of upper GI peptic ulcer bleeding (UGIB) associated with nonselective NSAIDs, aspirin, antiplatelet agents, and anticoagulants. METHODS: This case-control study matched 2,777 consecutive patients with UGIB (confirmed by endoscopy) with 5,532 controls (2:1). Adjusted relative risks (RR) of UGIB are reported. RESULTS: Proton pump inhibitors (PPIs) (RR 0.33, 95% confidence interval [CI] 0.27-0.39), H2-receptor antagonists (H2-RAs) (RR 0.65, 95% CI 0.50-0.85), and nitrates (RR 0.52, 95% CI 0.38-0.70) reduced UGIB risk. PPI use was associated with greater reductions among both traditional NSAID (RR 0.13, 95% CI 0.09-0.19 vs RR 0.30, 95% CI 0.17-0.53 with H2-RAs; RR 0.48, 95% CI 0.19-1.24 with nitrates) and low-dose aspirin users (RR 0.32, 95% CI 0.22-0.51 vs RR 0.40, 95% CI 0.19-0.73 with H2-RA; RR 0.69, 95% CI 0.36-1.04 with nitrates), and among patients taking clopidogrel (RR 0.19, 95% CI 0.07-0.49). For patients taking anticoagulants, use of nitrates, H2-RA, or PPIs was not associated with a significant effect on UGIB risk.

Нитраты, назначенные кардиопациентам на аспирине снижают риск ЖКК - это уже не первая публикация от испанцев, которая намекает The combination of both nitrate and low-dose aspirin was not associated with an increased risk of bleeding:

Lanas A,
Effects of nitrate and prophylactic aspirin on upper gastrointestinal bleeding: a retrospective case-control study.
J Int Med Res. 1998 Jun-Jul;26(3):120-8.

Lanas A,
Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding.
N Engl J Med. 2000 Sep 21;343(12):834-9

Это же отмечают и итальянцы:

Gallerani M, Simonato M, Manfredini R, Volpato S, Vigna GB, Fellin R; Investigators of the GIFA Study (Gruppo Italiano di Farmacovigilanza nell'Anziano).
Risk of hospitalization for upper gastrointestinal tract bleeding.
J Clin Epidemiol. 2004 Jan;57(1):103-10.

Известная протективная роль NO уже давно известна и не за горами то время когда выйдет на рынок нитро-аспирин (естественно цена его будет существенно отличаться от обычного).

Комбинация же аспирина с нитратами представляется достаточно оптимистичной, особенно у тех кардио-пациентов, которым нитраты могут быть показаны в лечении ИБС.

[alex_md]

Thanks, first time see this
Based of this observation just about anything you give with ASA will reduce the bleed :). I bet you, statins would reduce the risk too :). One explanation could be a confounding factor like CAD. Usually patients taking nitrates have CAD, right? CAD patient usually sees a doctor several times per year, has scopes, and frequent FOBT testing (each visit to the hospital and at least once a year in the office) etc. Would be interesting to see a prospective interventional study with nitrates.

[Dr.Vad]

Thanks, first time see this
Based of this observation just about anything you give with ASA will reduce the bleed :). I bet you, statins would reduce the risk too :).

Уважаемый Александр,

Вы были правы:

Am Heart J. 2006 May;151(5):976.e1-6.

Statins are associated with lower risk of gastrointestinal bleeding in patients with unstable coronary syndromes: analysis of the Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction 16 (OPUS-TIMI 16) trial

RESULTS: Inhospital GI bleeding rate was significantly lower in patients who were receiving lipid-lowering drugs before admission compared with those who were not (0.2% vs 0.6%, P = .031). Throughout 10 months of follow-up, GI bleeding occurred in 1.8% of non-statin users compared with 1.0% of statin users (P = .001). Statin use was associated with less overall bleeding in both the orbofiban (1.4% vs 2.4%, P = .006) and the placebo groups (0.2% vs 0.8%, P = .047). Severe and major bleeding occurred less frequently with statin use (0.8% vs 1.5%, P = .001) in both the orbofiban (1.1% vs 2.0%, P = .006) and the placebo groups (0.1% vs 0.5%, P = .119). Logistic regression analysis showed that age > 65 years, orbofiban treatment, Killip class > 1, history of cerebrovascular disease, and calcium-channel blocker use were associated with higher risk of GI bleeding, whereas statin therapy was associated with a lower risk (odds ratio 0.68, 95% CI 0.45-1.04, P = .079).

Правда обьясняющий механизм там другой, нежели Вы привели:

...we have recently demonstrated that atorvastatin increases myocardial content of PGI2 and PGE2 through increased expression and activity of phospholipase A2, cyclooxygenase 2, and PGI2 and PGE2 synthases. Chen et al have shown that statins induce cyclooxygenase 2 gene expression and PGE2 release in murine macrophages. Prostaglandins are known to protect the gastric mucosa and reduce the risk of GI bleeding. Assuming that an increase in systemic PGI2 and PGE2 production occurs with statins, there may be a protective effect exerted on GI bleeding by statins.

Вряд ли появятся репрезентативные работы по нитратам, когда нитро-НПВС уже на грани выхода на рынок (интересно, почему нужно обязательно изобретать новую молекулу, когда проще тестировать микс в одной таблетке?), вот механизмы противоязвенного действия нитратов:

The major importance of NO in the prevention of mucosal damage or in preservation of ulcer healing is supported by previous studies showing that both endogenous NO released by
capsaicin or NO originating from L-arginine, a substrate for NO-synthase (NOS), or that released from glyceryl trinitrate exert gastroprotective activity and accelerate healing mainly due to the maintenance of blood flow around the ulcer and enhancement of angiogenesis...enhanced mucosal expression of COX-2 at the ulcer margin contributes to ulcer healing and that NO released from gastric-sparing NO-NSAIDs derivatives can compensate with NO for PG deficiency induced by NSAID.(Dig Liver Dis. 2000 Oct;32(7):583-94)