Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study
© Barni et al; licensee BioMed Central Ltd. 2011
Received: 27 July 2011
Accepted: 20 October 2011
Published: 20 October 2011
Cancer patients receiving chemotherapy are at increased risk of thrombosis. Nadroparin has been demonstrated to reduce the incidence of venous and arterial thrombotic events (TEs) by about 50% in cancer outpatients receiving chemotherapy. The aims of this retrospective analysis were to evaluate the thromboembolic risk and the benefit of thromboprophylaxis according to type of chemotherapy.
Cancer outpatients were randomly assigned to receive subcutaneous injections of nadroparin or placebo. The incidence of symptomatic TEs was assessed according to the type of chemotherapy. Results were reported as risk ratios with associated 95% CI and two-tailed probability values.
769 and 381 patients have been evaluated in the nadroparin and placebo group, respectively. In the absence of thromboprophylaxis, the highest rate of TEs was found in patients receiving gemcitabine- (8.1%) or cisplatin-based chemotherapy (7.0%). The combination of gemcitabine and cisplatin or carboplatin increased the risk to 10.2%. Thromboprophylaxis reduced TE risk by 68% in patients receiving gemcitabine; with a further decrease to 78% in those receiving a combination of gemcitabine and platinum.
This retrospective analysis confirms that patients undergoing chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Our results also suggest that outpatients receiving chemotherapy regimens including these agents might achieve an increased benefit from thromboprophylaxis with nadroparin. Clinical Trial registration number: NCT 00951574
Keywordschemotherapy nadroparin prophylaxis thrombosis LMWH
Cancer patients are at increased risk of thrombosis . Thromboembolic complications may be the first manifestation of malignancy and are associated with a high rate of morbidity and mortality . Thromboembolic events (TEs) occur in 4-20% of patients with cancer . Evidences of thrombosis have been reported in up to 50% of cancer patients in autoptic series . TEs and infections are the second cause of death in cancer patients after the cancer itself .
Large studies have suggested that some solid malignancies including pancreatic, lung, colon, ovarian, primary hepatic and brain cancer are associated with a higher risk of TEs [6, 7]. Risk factors, such as age, gender, bed-rest, venous catheters, surgery, radiotherapy and infections, also increase the risk of thrombosis in cancer patients .
Epidemiological studies have identified chemotherapy as an additional risk factor for a hypercoagulability state and thrombosis . The pathophysiology of chemotherapy-related TEs may involve a variety of mechanisms that include enhanced procoagulant activity, reduced anticoagulant synthesis, stimulation of platelet aggregation and endothelial damage . In a population-based study, chemotherapy was associated with risk of venous TEs that was increased 6.5-fold compared to non-cancer patients . Platinum analogues, anthracyclines and fluoropyrimidines are agents mostly associated with a pro-thrombotic effect. In a prospective study, platinum-based regimens were significantly associated with venous TEs . Even within this class of agents, rates of TEs seem to be higher in patients receiving cisplatin compared to oxaliplatin . Gemcitabine has also been associated with remarkable thrombotic and vascular side effects . Lastly, venous thromboembolic disease and catheter-related thrombosis have been documented in patients receiving 5-fluorouracil [15–18]. The use of concomitant steroids, erythropoietin preparations and granulocyte colony-stimulating factors (G-CSF) has also been associated with an increased incidence of TEs in cancer patients .
Recently, Agnelli et al  demonstrated that nadroparin almost halved, from 3.9% to 2.0%, the absolute rate of thromboembolic complications. The overall amount of reduction in symptomatic outcomes is consistent with those attributable to low-molecular-weight heparin in prevention of venous thromboembolism in other clinical settings .
The PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) study highlighted chemotherapy as an independent risk factor for thromboembolism in a wide cancer population and defined the benefit of thromboprophylaxis . The PROTECHT results have not the impact to change current practice for TE prophylaxis in the overall ambulatory cancer population receiving chemotherapy, otherwise a selection of patients The aims of this retrospective analysis were to identify subgroups of patients at high risk of TEs, stratified according to the type of chemotherapy, who could have an enhanced benefit from TEs prophylaxis.
Patients and methods
Design of the PROTECHT Study
The PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) was a randomized, group sequential, placebo-controlled, double-blind, multicentre, clinical outcome study (NCT 00951574) . Outpatients with metastatic or locally advanced solid tumours were randomized in a 2:1 ratio to receive either subcutaneous injections of nadroparin (3800 anti-Xa IU once daily) or placebo. Study treatment was started on the same day as chemotherapy and was given for the duration of chemotherapy or up to a maximum of 120 days (+/- 10 days). The primary outcome was the composite endpoint of symptomatic venous or arterial thromboembolic events, as adjudicated by an independent committee. Major bleeding was the main safety outcome.
Retrospective analysis of the PROTECHT study population, according to type of chemotherapy and concomitant medications, was carried out. All cytotoxic agents used in ≥ 1% of patients were evaluated. All concomitant medications that might potentially interact with coagulation factors were evaluated: steroids, G-CSF, nonsteroidal anti-inflammatory drugs, aspirin, erythropoietin, blood and related products .
An evaluation of the TE risk according to Khorana score  has been evaluated. This predictive score assigns 2 points to very high risk cancer sites (pancreatic or gastric) or 1 point to high risk cancer sites (lung, ovarian or bladder). In addition, 1 point is assigned for each of the followings: platelet count > 350 × 109/L, hemoglobin < 10 g/dl and/or use of erythropoietin-stimulating agents, leukocyte count > 11 × 109/L and body mass index > 35 kg/m2. Patients with a score ≥ 3 are at high risk to develop TEs
The study was done in accordance with the provisions of the Declaration of Helsinki and local regulations. The protocol was approved by the institutional review board at each study centre, and written inform consent was obtained from all patients before randomization.
Descriptive statistics refer to all included patients. For continuous variables, the mean, standard deviation, median, minimum and maximum values were calculated. For each discrete variable, the number of cases in each category, in relation to all cases with non-missing values of that variable, was calculated.
Venous and arterial TE rates, grouped by the type of chemotherapy regimen, were reported as risk ratios (RRs) with associated two-tailed 95% CI. The approach adopted for the sub-group analyses consisted in considering findings as hypothesis-generating as a guide to prioritize additional studies. Hence, no adjustment of type I error rate was adopted for the multiplicity of confidence intervals over sub-groups. All statistical calculations were carried out using SAS version 9.1.
Nadroparin (N = 769)
Placebo (N = 381)
Mean ± SD
62.1 ± 10.3
63.7 ± 9.2
Median (Min - Max)
Head and Neck
Number of chemotherapy cycles
Mean ± SD
3.2 ± 1.4
3.4 ± 1.5
Median (Min - Max)
Central venous catheter
Khorana risk score and Khorana risk group evaluated among the PROTECHT patients
Nadroparin (N = 765*)
Placebo (N = 378*)
Khorana Risk score
Khorana Risk group*
In the nadroparin arm, chemotherapy regimens containing vinca alkaloids were statistically more frequent (11.7%, 90/769) than in the placebo arm (7.1%, 27/381), but no other differences were found for the other chemotherapeutic regimens.
Chemotherapy and concomitant medications by treatment group
Nadroparin (n = 769) % (n)
Placebo (n = 381) % (n)
P-value (two tailed)
Chemotherapy regimen containing a :
Concomitant Medication b
Blood and related products
Retrospective analysis results
Proportion of symptomatic TEs according to the type of chemotherapy regimen
Overall PROTECHT population
Chemotherapy regimen containing:
Proportion of symptomatic TEs in patients receiving a platinum-based regimens (cisplatin or carboplatin) in combination with gemcitabine, docetaxel or vinca alkaloids
Without vinca alkaloids
With vinca alkaloids
Antithrombotic prophylaxis with nadroparin reduced the risk of developing a TE in comparison to placebo in all chemotherapy regimens (Table 4). In particular, thromboprophylaxis reduced the risk of TEs in gemcitabine- (RR, 95%CI: 0.32, 0.09 - 1.04), carboplatin- (RR, 95%CI: 0.15, 0.02 - 1.45) and cisplatin- (RR, 95%CI: 0.32, 0.09 - 1.12) -containing regimens (Table 4). A relatively lower reduction in the risk of TEs was seen in 5-fluorouracil- (RR, 95%CI: 0.74, 0.24 - 2.3), vinca alkaloids- (RR, 95%CI: 0.60, 0.06 - 6.36) and oxaliplatin- (RR, 95%CI: 0.62, 0.04 - 9.83) -containing regimens.
Thromboprophylaxis also reduced the risk of TEs (RR, 95%CI: 0.22, 0.04 - 1.08) in patients treated with the combination of gemcitabine and platinum compounds, and in patients treated with vinca alkaloids and platinum compounds (RR, 95%CI: 0.28, 0.02 - 4.15) (Table 5).
Proportion of symptomatic TEs according to concomitant medication
Blood and related products
In the PROTECHT study , nadroparin was shown to reduce the absolute rate of clinically overt TEs by about 50% in cancer outpatients receiving chemotherapy for metastatic or locally advanced solid tumors in comparison to placebo. Despite the results of the PROTECHT study thromboembolic prophylaxis could not be reasonable for the whole ambulatory cancer patients receiving chemotherapy. To improve the risk-benefit ratio of thromboprophylaxis, clinicians should identify patients at higher risk of TEs, who could have more benefit from anticoagulant administration. The aim of our retrospective analysis has been to identify in the PROTECHT population which subgroups of patients were at higher risk of TEs, stratified according to the type of chemotherapy, who could have an enhanced benefit from TEs prophylaxis.
Our results suggest that cancer outpatients receiving chemotherapy in the absence of thromboprophylaxis (placebo group) had a high incidence of TEs during treatment with gemcitabine, cisplatin or carboplatin. Etoposide and epirubicin showed also a high rate of TEs, but in a small subgroup of patients. Among platinum agents, cisplatin and carboplatin showed a higher risk of TE complications in comparison to oxaliplatin. Combination therapy of gemcitabine with platinum-compounds (cisplatin or carboplatin) further increased the risk of TEs. Additionally, the combination docetaxel with platinum compounds appeared to increase the risk of TEs, although the sample size was too small to make any definitive conclusions.
The thromboembolic risk of cisplatin and gemcitabine has been previously described [14, 15]. In vitro studies have demonstrated that cisplatin activates platelets, mononuclear cells and endothelial cells, which together may result in a prothrombotic state ; however, the exact role of gemcitabine in the activation of the coagulation cascade and haemostasis remains unknown . Published case series, isolated reports and observational studies have suggested that gemcitabine, particularly if combined with cisplatin, increases the risk of TEs [28–30]. Cisplatin is already known as a chemotherapy drug with a higher thromboembolic risk in comparison to oxaliplatin [13, 31]. Recently, Moore and colleagues published a large retrospective analysis which confirmed an unacceptable incidence of TEs in cancer patients receiving cisplatin-based chemotherapy .
At the time of the enrolment in the PROTECHT study, targeted therapies were not commonly used in cancer patients. In fact, only 4.2% (48/1150) of patients were treated with trastuzumab, cetuximab or bevacizumab. Nonetheless, it is worthwhile noting that the CALGB 80303 trial  recently compared bevacizumab plus gemcitabine versus gemcitabine alone in patients with advanced pancreatic cancer. In that trial, the rates of grade 3/4 venous thrombosis was similar in both arms (14% and 15%, respectively) suggesting that the role of gemcitabine in cancer-induced thrombosis could be prevalent. Of note that currently, the efficacy of thromboprophylaxis in patients receiving antiangiogenic agents remains an open questions to be evaluated in well-designed randomized trials.
According to published data , the rate of TEs is more than two-fold higher in chemotherapy naïve patients (5.2%, 11/213) compared to non-naïve patients (2.4%, 4/168). Nadroparin prophylaxis shown a trend in reduction for thromboembolic risk by 52% and 42% in naïve and non-naïve patients, respectively.
The results in the global PROTECHT population have shown that thromboprophylaxis reduced the risk of developing TEs by 48.8% compared to placebo (. Considering the subgroup of patients receiving cisplatin or carboplatin, thromboprophylaxis reduced the risk of thrombotic complications by 68% and 85%, respectively. Thromboprophylaxis reduced risk of thromboembolic complications in patients receiving gemcitabine by 68%, further decreasing to 78% when gemcitabine was combined with platinum-compounds.
Our retrospective analysis has an exploratory purpose. Subgroup samples have not the adequate statistical power to detect clinically meaningful differences as statistically significant and to adjust p-values for the multiplicity across subgroups . For the same reason, a multivariable analysis testing the interaction between subgroups and study treatment cannot be performed because such a statistical model would be clearly over-parameterized. Nevertheless and despite the aforementioned limitations  these data could be useful for stratifying the TE risk in ambulatory cancer population, when planning controlled clinical studies.
In conclusion, our results suggest that patients receiving gemcitabine, cisplatin or carboplatin or their combination are at increased risk of TEs. The clinical benefit of thromboprophylaxis with nadroparin, in outpatients receiving chemotherapy, could be even more evident when gemcitabine was combined with platinum-compounds containing regimens.
We are indebted to Gualberto Gussoni, Milan, Italy and Anna Falanga, Bergamo Italy for their scientific support and to the PROTECHT's investigators.
- Blom JW, Vanderschoot JP, Oostindiër MJ, Osanto S, van der Meer FJ, Rosendaal FR: Incidence of venous thrombosis in a large cohort of 66329 cancer patients: results of a record linkage study. J Thromb Haemost. 2006, 4: 529-35. 10.1111/j.1538-7836.2006.01804.x.View ArticlePubMed
- White RH, Chew HK, Zhou H, Parikh-Patel A, Harris D, Harvey D, Wun T: Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med. 2005, 165: 1782-7. 10.1001/archinte.165.15.1782.View ArticlePubMed
- Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH, Somerfield MR, Einhaus K, Hagerty KL, Brouwers MC: Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007, 5: 632-4. 10.1111/j.1538-7836.2007.02374.x.View ArticlePubMed
- Schwartz JD, Simantov R: Thrombosis and malignancy: pathogenesis and prevention. In Vivo. 1998, 12: 619-24.PubMed
- Haddad TC, Greeno EW: Chemotherapy-induced thrombosis. Thromb Res. 2006, 118: 555-68. 10.1016/j.thromres.2005.10.015.View ArticlePubMed
- Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL: The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med. 1998, 338: 1169-73. 10.1056/NEJM199804233381701.View ArticlePubMed
- Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999, 78: 285-91. 10.1097/00005792-199909000-00001.View Article
- Khorana AA, Francis CW, Culakova E, Lyman GH: Risk factors for chemotherapy-associated venous thromboembolism in prospective observational study. Cancer. 2005, 104: 2822-29. 10.1002/cncr.21496.View ArticlePubMed
- Nadir Y, Hoffman R, Brenner B: Drug-related thrombosis in hematologic malignancies. Rev Clin Exp Hematol. 2004, 8: E4-PubMed
- Blom JW, Doggen CJ, Osanto S, Osendaal FR: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005, 293 (6): 715.-10.1001/jama.293.6.715.View ArticlePubMed
- Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ: Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000, 160 (6): 809-10.1001/archinte.160.6.809.View ArticlePubMed
- Kröger K, Weiland D, Ose C, Neumann N, Weiss S, Hirsch C, Urbanski K, Seeber S, Scheulen ME: Risk factors for venous thromboembolic events in cancer patients. Ann Oncol. 2006, 17: 297-303.View ArticlePubMed
- Starling N, Rao S, Cunningham D, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR: Thromboembolism in patients with advanced gastroesophageal cancer treated with anthracycline, platinum, and fluoropyrimidine combination chemotherapy: A report from the UK National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group. J Clin Oncol. 2009, 27: 3786-3793. 10.1200/JCO.2008.19.4274.View ArticlePubMed
- Dasanu CA: Gemcitabine: Vascular toxicity and prothrombotic potential. Expert Opin Drug Saf. 2008, 7 (6): 703-16. 10.1517/14740330802374262.View ArticlePubMed
- Doll DC, Ringenberg QS, Yarbro JW: Vascular toxicity associated with antineoplastic agents. J Clin Oncol. 1986, 4: 1405-1417.PubMed
- Tham J, Albertsson M: Upper extremity deep venous thrombosis in patients with 5-fluorouracilcontaining adjuvant chemotherapy--three case reports and a review. Acta Oncol. 2004, 43: 108-112. 10.1080/02841860310021545.View ArticlePubMed
- Blom JW, Osanto S, Rosendaal FR: High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients. Eur J Cancer. 2006, 42: 410-414. 10.1016/j.ejca.2005.09.013.View ArticlePubMed
- Yoshikawa R, Yanagi H, Noda M, Ikeuchi H, Nakano H, Gega M, Tsukamoto K, Oshima T, Inoue T, Fujiwara Y, Shoji Y, Sakaki T, Higasa S, Hashimoto-Tamaoki T, Yamamura T: Venous thromboembolism in colorectal cancer patients with central venous catheters for 5-FU infusion-based pharmacokinetic modulating chemotherapy. Oncol Rep. 2005, 13: 627-632.PubMed
- Agnelli G, Gussoni G, Bianchini C, Verso M, Mandalà M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M, PROTECHT Investigators: Nadroparin for the prevention of thromboembolic events in outpatients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 2009, 10 (10): 943-9. 10.1016/S1470-2045(09)70232-3.View ArticlePubMed
- Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW, American College of Chest Physicians: Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2008, 133: 381S-453S. 10.1378/chest.08-0656. 8View ArticlePubMed
- Noble S: A step in the right direction, but one size might not fi t all. Lancet Oncol. 2009, 10 (10): 930-1. 10.1016/S1470-2045(09)70293-1.View ArticlePubMed
- Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW: Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008, 111 (10): 4902-4907. 10.1182/blood-2007-10-116327.PubMed CentralView ArticlePubMed
- Cohen AT, Nandini B, Wills JO, Ota S: VTE prophylaxis for the medical patient: where do we stand? - a focus on cancer patients. Thromb Res. 2010, 125 (Suppl 2): S21-9.View ArticlePubMed
- Agnelli G, Verso M: Thromboprophylaxis during chemotherapy in patients with advanced cancer. Thromb Res. 2010, 125 (Suppl 2): S17-20.View ArticlePubMed
- Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ: Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol. 2009, 27 (29): 4865-73. 10.1200/JCO.2009.22.3875.View ArticlePubMed
- Kuenen BC, Levi M, Meijers JC, van Hinsbergh VW, Berkhof J, Kakkar AK, Hoekman K, Pinedo HM: Potential role of platelets in endothelial damage observed during treatment with cisplatin, gemcitabine, and the angiogenesis inhibitor SU5416. J Clin Oncol. 2003, 21: 2192-8. 10.1200/JCO.2003.08.046.View ArticlePubMed
- Zecchina G, Ghio P, Bosio S, Cravino M, Camaschella C, Scagliotti GV: Reactive thrombocytosis might contribute to chemotherapy-related thrombophilia in patients with lung cancer. Clin Lung Cancer. 2007, 8: 264-7. 10.3816/CLC.2007.n.004.View ArticlePubMed
- Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, Trochanowski B, Tarassoff PG: Phase II trial of gemcitabine (2,2'-difl uorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs. 1994, 12: 29-34. 10.1007/BF00873232.View ArticlePubMed
- Dumontet C, Morschhauser F, Solal-Celigny P, Bouafia F, Bourgeois E, Thieblemont C, Leleu X, Hequet O, Salles G, Coiffier B: Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin's lymphoma. Br J Haematol. 2001, 113: 772-8. 10.1046/j.1365-2141.2001.02795.x.View ArticlePubMed
- Numico G, Garrone O, Dongiovanni V, Silvestris N, Colantonio I, Di Costanzo G, Granetto C, Occelli M, Fea E, Heouaine A, Gasco M, Merlano M: Prospective evaluation of major vascular events in patients with nonsmall cell lung carcinoma treated with cisplatin and gemcitabine. Cancer. 2005, 103: 994-9. 10.1002/cncr.20893.View ArticlePubMed
- Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E, Arbeitsgemeinschaft Internistische Onkologie Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008, 26 (9): 1435-42. 10.1200/JCO.2007.13.9378.View ArticlePubMed
- Moore RA, Adel N, Riedel E, Bhutani M, Feldman DR, Tabbara NE, Soff G, Parameswaran R, Hassoun H: High incidence of thromboembolic events in patients treated with Cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol. 2011, 29 (25): 3466-73. 10.1200/JCO.2011.35.5669.View ArticlePubMed
- Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM: Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010, 28 (22): 3617-22. 10.1200/JCO.2010.28.1386.PubMed CentralView ArticlePubMed
- Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM: Statistics in medicine - reporting of subgroup analyses in clinical trials. N Engl J Med. 2007, 357: 2189-94. 10.1056/NEJMsr077003.View ArticlePubMed
- Cook DI, Gebski VJ, Keech AC: Subgroup analysis in clinical trials. MJA. 2004, 180 (6): 289-291.PubMed
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