Interact CardioVasc Thorac Surg 2007;6:534-537. doi:10.1510/icvts.2007.157941
© 2007 European Association of Cardio-Thoracic Surgery
Best evidence topic - Cardiac general |
Does clopidogrel rather than aspirin plus a proton-pump inhibitor reduce the frequency of gastrointestinal complications after cardiac surgery?
Maren Ziegelina,
Andreas Hoschtitzkya,*,
Joel Dunningb and
Tim Hoopera
a Department of Cardiothoracic Surgery, Wythenshawe Hospital, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Received 17 April 2007;
accepted 18 April 2007
*Corresponding author. Tel.: +44-161-2912511; fax: +44-161-2912522.
E-mail address: ahoschtitzky{at}yahoo.com (A. Hoschtitzky).
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Abstract
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A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether clopidogrel rather than aspirin plus a proton-pump inhibitor reduce the frequency of gastrointestinal complications after cardiac surgery. Altogether 40 publications were identified using the below-mentioned search and all the papers reference lists were searched. Six papers presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. We conclude that clopidogrel causes fewer gastrointestinal complications than aspirin in those patients with no previous history of gastric or duodenal ulceration with a number needed to treat of around 200 to prevent an episode of bleeding per year. However, in those patients with a previous history of gastrointestinal complications, clopidogrel alone is not a safer alternative than aspirin alone. Either aspirin or clopidogrel combined with a proton pump inhibitor are equally effective for these patients.
Key Words: Clopidogrel; Aspirin; Proton-pump inhibitor; Cardiac surgery; Gastrointestinal complications
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1. Introduction
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A best evidence topic was constructed according to the structured protocol. This protocol is fully described in the ICVTS [1].
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2. Clinical scenario
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You are seeing a 72-year-old man eight days post-CABG. He had some melaena on day 2 and endoscopy showed a duodenal ulcer, which was injected. He has had no more symptoms or signs of continued bleeding and you would like to resume anti-platelet therapy. You have heard that clopidogrel is better for your stomach and decide to restart this instead of aspirin, but later that day the endoscopist reviews the patient and suggests that aspirin and lansoprazole would be safer and cheaper too. You resolve to check this in the literature.
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3. Three-part question
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In patients undergoing [cardiac surgery] is [clopidogrel superior to aspirin and a proton-pump inhibitor] for the prevention of [gastrointestinal bleeding or complications or peptic ulcers]?
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4. Search strategy
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Medline 1966–November 2006 using the OVID interface.
[clopidogrel.mp] AND [exp Aspirin/OR aspirin.mp] AND [exp Gastrointestinal Hemorrhage/OR gastrointestinal bleed$.mp OR exp Peptic Ulcer Hemorrhage/OR exp Peptic Ulcer Perforation/OR exp Duodenal Ulcer/OR exp Peptic Ulcer Hemorrhage/OR exp Peptic Ulcer/OR Gastrointestinal ulcer.mp OR exp Stomach Ulcer/].
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5. Search outcome
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A total of 40 papers were found. All relevant papers had their reference list crosschecked. From this search six papers were deemed to represent the best evidence on the topic. The papers are summarised in Table 1.
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6. Discussion
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Chan et al. [2] performed a randomised controlled trial of 320 patients which was published in the New England Journal of Medicine. They showed that in patients with previous upper gastrointestinal (GI) bleeding there was a significant risk reduction if aspirin plus a proton-pump inhibitor (PPI) was used compared to clopidogrel alone (P=0.001, NNT 13). There was no risk reduction in lower GI bleeding which is likely to have been due to the effects of PPIs being confined to the upper GI. Chan et al. demonstrated significant superiority in upper GI bleeding prevention for aspirin plus a proton-pump inhibitor vs. clopidogrel alone.
Ibanez et al. [3] performed a case control study of 9841 patients. This study, comparing patients with previous GI bleeding with matched controls, demonstrated an increased risk of upper GI bleeding in patients on aspirin (OR 4.0, CI 3.2–4.9) vs. clopidogrel (OR 2.3, CI 0.9–6.0). There was a decreased risk of upper GI bleeding in patients on aspirin plus a PPI (OR 1.1, CI 0.5–2.6) vs. patients on aspirin alone (OR 4.0, CI 3.2–4.9). PPI used simultaneously with a non-aspirin anti-platelet drug, showed a similar decrease in risk profile from OR 2.1 (1.5–2.9) to OR 0.9 (0.4–2.3). Therefore, an increased risk of aspirin alone vs. clopidogrel was demonstrated, but a decreased risk for aspirin plus a PPI. The risk of upper GI bleeding seems to be lowest with aspirin plus a PPI.
The study from Ng et al. [4] included 129 patients on low-dose aspirin with minor peptic ulcer disease. The trial compared aspirin in combination with PPI vs. a group which discontinued aspirin and replaced this with clopidogrel plus PPI. The end-point was endoscopically proven ulcer healing within eight weeks. There was no evidence of peptic ulcer complication in either group. Three patients in the aspirin arm had ongoing minor peptic ulcer disease compared to four patients in the clopidogrel group. This study suggests that both aspirin and clopidogrel plus a PPI are equally safe considering peptic ulcer complications. This study was unfortunately small, excluded high risk patients and only measured up to eight weeks treatment effect and a bigger trial is, therefore, needed to verify the results with a longer follow-up time.
Lai et al. [5] included 170 patients on low-dose aspirin in their study with previous peptic ulcer bleeding. The patients were randomized into two groups. One group received aspirin plus a PPI and the other group received clopidogrel alone. None of the patients in the aspirin arm had peptic ulcer complications vs. nine patients in the clopidogrel group [OR 13.6 (CI 6.3–20.9), P=0.0019]. In this trial aspirin plus a PPI was demonstrably superior to clopidogrel alone.
Ng et al. [6] retrospectively studied 70 patients with either a previous history of non-aspirin-related peptic ulceration or aspirin-related GI complications (dyspepsia or peptic ulcer). All 70 participants were given clopidogrel. None of the patients were on maintenance PPI treatment. Nine (12%) patients had GI bleeding and one patient had a perforated ulcer. This study demonstrated a significant increase in peptic ulcer bleeding in patients with a history of GI bleeding vs. patients without a history of peptic ulcers whilst on clopidogrel (P=0.007; OR 1.3, CI 1.1–1.5).
The CAPRIE-Trial [7] involved 19,185 patients with previous ischaemic stroke, MI or atherosclerotic peripheral disease. One arm of the study received aspirin and the other clopidogrel. The end-point was occurrence of ischaemic stroke, MI or vascular death. The outcome was a significant risk reduction for clopidogrel vs. aspirin of 8.7% (P=0.043; CI 0.3–16.5). The annual risk for complications was 5.32% (clopidogrel) and 5.83% (aspirin), respectively. GI bleeding was found in 191 patients (1.99%) on clopidogrel vs. 255 (2.66%) on aspirin (RR 1.34, CI 1.11–1.61, P<0.05). Therefore, they demonstrated a significant reduction of GI bleeding with clopidogrel in patients with previous cardiovascular events.
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7. Clinical bottom line
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Clopidogrel causes fewer gastrointestinal complications than aspirin in those patients with no previous history of gastric or duodenal ulceration with a number needed to treat of around 200 to prevent an episode of bleeding per year. However, in those patients with a previous history of gastrointestinal complications, clopidogrel alone is not a safer alternative than aspirin alone. Either aspirin or clopidogrel combined with a proton-pump inhibitor are equally effective for these patients.
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References
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- Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.[Abstract/Free Full Text]
- Chan FKL, Ching JYL, Hung LCT, Wong VWS, Leung VKS, Kung NNS, Hui AJ, Wu JCY, Leung WK, Lee VWY, Lee KKC, Lee YT, Lau JYW, To KF, Chan HLY, Chung SCS, Sung JJY. Clopidogrel vs. aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005; 352:238–244.[Abstract/Free Full Text]
- Ibanez L, Vidal X, Vendrell L, Moretti U, Laporte JR. On behalf of the Spanish-Italian collaborative group for the epidemiology of gastrointestinal bleeding. Upper gastrointestinal bleeding associated with antiplatelet drugs. Aliment Pharmacol Ther 2006; 23:235–242.[CrossRef][Medline]
- Ng FH, Wong BCY, Wong SY, Chen WH, Chang CM. Clopidogrel plus omeprazole compared with aspirin plus omeprazole for aspirin-induced symptomatic peptic ulcers/erosions with low to moderate bleeding/re-bleeding risk – a single-blind, randomized controlled study. Aliment Pharmacol Ther 2004; 9:359–365.
- Lai KC, Chu KM, Hui WM, Wong BCY, Hung WK, Loo CK, Hu WHC, Chan AOO, Kwok KF, Fung TT, Wong J, Lam SK. Esomeprazole with aspirin vs. clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clinical Gastroenterology and Hepatology 2006; 4:860–865. [Abstract].[CrossRef]
- Ng FH, Wong SY, Chang CM, Chen WH, Kng C, Lanas AI, Wong BCY. High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther 2003; 18:443–449.[CrossRef][Medline]
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L. K. von Segesser
Interactive CardioVascular and Thoracic Surgery (ICVTS) has been selected to be indexed and included in MEDLINE/PubMed
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October 1, 2007;
6(5):
579 - 579.
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Abstract
1. Introduction