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Three Part Question

In [patients with suspected cardiac chest pain] does [measurement of soluble plasma P-selectin] allow [exclusion of acute coronary syndrome]?

Clinical Scenario

A fifty year-old man presents to the Emergency Department with a two-hour history of dull central chest pain. Past history includes a coronary artery bypass graft six years ago following MI but no subsequent angina. He had a peptic ulcer two years ago. ECG shows some non-specific T wave flattening in the lateral leads. Judging him to be high risk, you follow your department protocol, refer for troponin testing at 12 hours and administer aspirin, clopidogrel, dalteparin, atenolol and pravastatin.
You wonder if there is any evidence that measurement of P-selectin, a promising cardiac marker you have heard about, would aid your triage decision, perhaps enabling early discharge without the need for potentially unnecessary and risky treatment.

Search Strategy

OVID Medline 1966 - 2005 August Week 1
OVID Embase 1980 - 2005 Week 34
The Cochrane Library 2005 Issue 2
OVID:
[exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR exp Angina, Unstable/ OR (myocard$ adj (infarct$ OR ischaem$ OR ischem$)).mp. OR (acute coronary syndrome OR unstable angina OR ACS OR AMI OR MI).mp.] AND [exp P-Selectin/ OR (p selectin OR GMP-140 OR PADGEM OR CD62P).mp. limit to human and English language
Cochrane:
(Myocardial Infarction [MeSH] OR Angina, Unstable [MeSH] OR (myocard* NEAR (infarct* OR ischaem* OR ischem*) OR acute coronary syndrome OR ACS OR AMI OR MI) AND (p selectin OR GMP-140 OR PADGEM OR CD62P)

Search Outcome

222 papers were identified using Medline, 5 of which were relevant.
280 papers were identified using Embase, 4 of which were relevant.
8 papers were identified using Cochrane, none of which were relevant.
In total, five papers were relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gurbel et al 2000 United States	122 consecutive patients presenting to the Emergency Department with suspected cardiac chest pain within 24 hours of onset, plus 14 healthy controls. Blood taken in the Emergency Department before reperfusion or other intensive therapies. Follow up at 30 days	Prospective observational cohort	Plasma P-selectin and diagnosis	Significantly higher in AMI, UA and heart failure than non-cardiac pain and controls (p<0.05 for all).	Outdated gold standard diagnosis of MI (CK-MB not troponin was utilised as the biochemical marker of choice). Time from symptom onset to blood sampling not standardised or reported. Despite following patients up at 30 days, no clinical follow up data reported.
			Cut-off of 120ng/ml for detection of cardiac pain	Sensitivity 55.8% (95% CI 0.457-0.655); Specificity 55.3% (95% CI 0.447-0.656); PPV 0.580 (95% CI 0.477-0.677), NPV 0.530 (95% CI 0.427-0.632).
Hollander et al 1999 United States	263 consecutive patients presenting to the Emergency Department with suspected cardiac chest pain of <6 hours duration. Blood taken at presentation ("approximately 3 hours" after symptom onset) and after 1 hour. Follow up at 30 days.	Prospective observational cohort	Soluble P-selectin for diagnosis of MI	Area under ROC curve 0.646 (CK-MB 0.721, P=0.086). At the optimal cut-off of 138.8ng/ml, sensitivity 45%, specificity 76%, PPV 15%, NPV 94% (CK-MB sensitivity 50%, NPV 95%).	Time of blood sampling not standardised or objectively reported. Outdated gold standard diagnosis for AMI (CK-MB not troponin).
			Soluble P-selectin for diagnosis of ACS	Area under ROC curve 0.583 (CK-MB 0.670, P=0.01). At the optimal cut-off of 138.8ng/ml, sensitivity 35%, specificity 79%, PPV 44%, NPV 71% (CK-MB sensitivity 26%, NPV 68%).
			Addition of serial sampling at 1 hour	Did not significantly affect the sensitivity, specificity , PPV and NPV
			Soluble P-selectin for prediction of serious cardiac events at follow up	Area under ROC curve 0.539 (CK-MB 0-.587, P=0.236). At the optimal cut-off of 138.8ng/ml, sensitivity 35%, specificity 76%, PPV 28%, NPV 82% (CK-MB sensitivity 29%, NPV 82%).
Hillis et al 2002 United States	126 consecutive patients admitted to a Medical Centre with suspected cardiac chest pain within the previous 24 hours. Blood taken on presentation to the Emergency Department. 113 patients (89.7%) completed follow up at 3 months.	Prospective observational cohort study	Soluble P-selectin and SCE during follow-up	Mean 66ng/ml among those with SCE; mean 47 without SCE (p=0.06). (TnI also predictive, P<0.001).	Index diagnoses not reported. Insufficient data reported to allow calculation of percentage of patients with -ve TnI who would be correctly identified as at risk using P-selectin levels. Small numbers.
			Independent predictors of SCE following logistic regression analysis	P-selectin (P<0.001, OR 1.005 (1.003-1.007)) and TnI (P<0.001, OR 1.018 (1.008-1.028)) were independent predictors.
			ROC curve analysis of P-selectin for prediction of SCE	Area under curve 0.66 (0.78 for TnI).
Serebruany et al 2001 Netherlands	122 consecutive patients admitted to the Chest Pain Centre of the Emergency Department within 24 hours of experiencing suspected cardiac chest pain.	Prospective observational cohort study	Soluble P selectin for diagnosis of AMI	C index (area under ROC curve) 0.562. Not an independent predictor on multivariate analysis (P=0.547).	Diagnosis of non-cardiac pain apparently according to treating physician's discretion with no objective verification. No clinical follow-up data. Data not reported in an easily interpretable or clinically meaningful manner. Increasing age in the CHF group may have influenced the results (P-selectin may rise with age).
			Soluble P-selectin for diagnosis of unstable angina	C index 0.506. Not an independent predictor on multivariate analysis (P=0.495).
			Soluble P-selectin for diagnosis of CHF	C index 0.668. An independent predictor on multivariate analysis (P=0.005).
			Soluble P-selectin for diagnosis of cardiac origin	C index 0.587. Not an independent predictor on multivariate analysis (P=0.311; notably platelet P-selectin was an independent predictor, P=0.002).
Serebruany et al 1999 United States	44 patients, of whom 13 presented to the Emergency Department and were diagnosed with AMI, 17 who presented to the Emergency Department with non-cardiac chest pain and 14 age- and sex-matched controls. Blood taken on admission for P-selectin, PECAM-1 and osteonectin.	Prospective observational cohort	P-selectin levels according to diagnosis	No significant difference between AMI and non-cardiac chest pain (149.5 +/- 49.8 ng/ml vs. 118.2 +/- 40.1 ng/ml).	Small numbers. No clinical follow-up data. Results not dichotomised to allow calculation of sensitivity, specificity, PPV, NPV and LR's.

Comment(s)

There is growing evidence that interaction between platelets, leucocytes and the endothelium may be pivotal in the pathogenesis of ACS (Ott et al, 1996; Sarma et al, 2002; Freedman et al, 2002). P-selectin, a cell adhesion molecule expressed by activated platelets and endothelial cells, may play a key role in mediating this interaction. P-selectin causes platelet-leucocyte interaction, encouraging migration of monocytes into atheroma and upregulating expression of the procoagulant tissue factor (Celi et al, 1994). It is also likely that P-selectin is necessary for the formation of large, stable, platelet-rich thrombus. Expression of P-selectin has been demonstrated in atherosclerotic, but not normal, endothelial cells (Johnson-Tidey et al, 1994; Koyama et al, 2003), and levels are further increased in unstable angina (Tenaglia et al, 1997). A soluble form of P-selectin is detectable in plasma, probably as a result of cleavage from activated platelets and endothelial cells (Blann et al, 2003). Thus detection of raised levels may be expected in ACS. Several investigators have demonstrated significantly increased P-selectin levels in AMI (Ikeda et al, 1994; Shimomura et al, 1998; Gurbel et al, 2001; Mulvihill et al, 2000; Xu et al, 1998; Guray et al, 2004), UA (Ikeda et al, 1995; Atalar et al, 2001; Parker et al, 2001) and all ACS (Aultet al, 1999; Itoh et al, 1995), although one group reported conflicting results (Soeki et al, 2003). In addition, one study reported that P-selectin identified patients at risk of recurrent events following ACS (Itoh et al, 1995) and, although another group reported conflicting results, they measured serum and not plasma levels, which may account for the difference (Mulvihill et al, 2001). Five studies have investigated the utility of P-selectin for diagnosis of ACS in the Emergency Department population. One small study of 44 patients found no difference in plasma soluble P-selectin between patients diagnosed with ACS and non-cardiac pain (Serebruany et al, 1999). Although one group reported that P-selectin was not an independent predictor for a diagnosis of ACS (Serebruany et al, 2001), another group reported that P-selectin was an independent predictor for the occurrence of serious cardiac events within 3 months of presentation to the Emergency Department with chest pain (Hilllis et al, 2001). Other groups have reported sensitivities of 35-55.8% and NPV's of 53-71% for the detection of cardiac chest pain (Hollander et al, 1999; Gurbel et al, 2000). The data suggests that the use of soluble P-selectin as a sole rule-out strategy for ACS in the Emergency Department is likely to lead to an unacceptably high false negative rate. However, data from large studies is lacking. In addition, combination of P-selectin with clinical and electrocardiographic data, markers of myocardial necrosis and other early cardiac markers may enable superior risk stratification and earlier discharge than is possible using current strategies. Further research is necessary.

Editor Comment

Abbreviations: ACS: acute coronary syndrome; MI: myocardial infarction; AMI: acute myocardial infarction; UA: unstable angina; SCE: serious cardiac event; PPV: positive predictive value; NPV: negative predictive value; LR: likelihood ratio; CI: confidence interval; ROC: receiver operating characteristic

Clinical Bottom Line

P-selectin is probably insufficiently sensitive to be used as a sole rule out strategy for ACS in the Emergency Department. However, incorporation into a multimarker strategy may improve the power of this diagnostic test.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Gurbel PA; Kereiakes DJ; Dalesandro MR; Bahr R; O'Connor CM; Serebruany L. Role of soluble and platelet-bound P-selectin in discriminating cardiac from noncardiac chest pain at presentation in the emergency department American Heart Journal 2000; 139: 320-328
2. Hollander JE; Muttreja R; Dalesandro MR; Shofer FS. Risk stratification of Emergency Department patients with acute coronary syndromes using P-selectin Journal of the American College of Cardiology 1999; 34(1): 95-105
3. Hillis GS; Terregino C; Taggart P; Killian A; Zhao N; Dalsey WC; Mangione A. Elevated soluble P-selectin levels are associated with an increased risk of early adverse events in patients with presumed myocardial ishcaemia American Heart Journal 2002; 143: 235-241
4. Serebruany VL; Levine DJ; Nair GV; Meister AF; Gurbel PA. Usefulness of combining necrosis and platelet markers in triaging patients presenting with chest pain to the Emergency Department Journal of Thrombosis and Thrombolysis 2001; 11: 1155-162
5. Serebruany VL; Murugesan SR; Pothula A; Semaan H; Gurbel PA Soluble PECAM-1, but not P-selectin, nor osteonectin identify acute myocardial infarction in patients presenting with chest pain Cardiology 1999; 91(1): 50-55
6. Ott I; Neumann FJ; Gawaz M; Schmitt M; Schomig A. Increased neutrophil-platelet adhesion in patients with unstable angina Circulation 1996; 94: 1239-1236
7. Sarma J, Laan CA, Alam S, Jha A, Fox KAA, Dransfield I Increased platelet binding to circulating monocytes in acute coronary syndromes Circulation 2002; 105: 2166-2171
8. Freedman JE,.Loscalzo J Platelet-monocyte aggregates: Bridging thrombosis and inflammation Circulation 2002; 105: 2130-2132
9. Celi A; Pellegrini G; Lorenzet R; De Blasi A; Ready N; Furie BC; Furie B P-selectin induces the expression of tissue factor on monocytes Proc Natl Acad Sci USA 1994; 91: 8767-8771
10. Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques American Journal of Pathology 1994; 144: 952-961
11. Tenaglia AN, Buda AJ, Wilkins RG; Barron MK; Jeffords PR; Vo K; Jordan MO; Kusnick BA; Lefer DJ Levels of expression of P-selectin, E-selectin and inter cellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris American Journal of Cardiology 1997; 79: 742-747
12. Koyama H, Maeno T, Fukumoto S, Shoji T, Yamane T, Yokoyama H; Emoto M; Shoji T; Tahara H; Inaba M; Hino M; Shioi A; Miki T; Nishizawa Y Platelet P-selectin expression is associated with atherosclerotic wall thickness in carotid artery in humans Circulation 2003; 108: 524-529
13. Blann AD, Nadar SK, Lip GYH The adhesion molecule P-selectin and cardiovascular disease European Heart Journal 2003; 24: 2166-2179
14. Ikeda H; Nakayama H; Oda T; Kuwano K; Muraishi A; Sugi K; Koga Y; Toshima H Soluble form of P-selectin in patients with acute myocardial infarction Coronary Artery Disease 1994; 5: 515-518
15. Shimomura H; Ogawa H; Arai H; Moriyama Y; Takazoe K; Hirai N; Kaikita K; Hirashima O; Misumi K; Soejima H; Nishiyama K; Yasue H Serial changes in plasma levels of soluble P-selectin in patients with acute myocardial infarction American Journal of Cardiology 1998; 81: 397-400
16. Gurbel PA, O'Connor CM, Dalesandro MR, Serebruany VL Relation of soluble and platelet P-selectin to early outcome in patients with acute myocardial infarction after thrombolytic therapy American Journal of Cardiology 2001; 87: 774-777
17. Mulvihill NT, Foley JB, Murphy R, Crean P, Walsh M . Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction Journal of the American College of Cardiology 2000; 36: 1210-1216
18. Xu DY, Zhao SP, Peng WP Elevated plasma levels of soluble P-selectin in patients with acute myocardial infarction and unstable angina: An inverse link to lipoprotein(a) International Journal of Cardiology 1998; 64: 253-258
19. Guray U; Erbay AR; Guray Y; Yilmaz B; Boyaci AA; Sasmaz H; Korkmaz S; Kutuk E Levels of soluble adhesion molecules in various clinical presentations of coronary atherosclerosis International Journal of Cardiology 2004; 96: 235-240
20. Ikeda H, Takajo Y, Ichiki K, Ueno T, Maki S, Noda T; Sugi K; Imaizumi T Increased soluble form of P-selectin in patients with unstable angina Circulation 1995; 92: 1693-1696
21. Atalar E; Aytemir K; Haznedaroglu I; Ozer N; Ovunc K; Aksoyek S; Kes S; Kirazh S; Ozmen F Increased plasma levels of soluble selectins in patients with unstable angina International Journal of Cardiology 2001; 78: 69-73
22. Parker C 3rd; Vita JA; Freedman JE Soluble adhesion molecules and unstable coronary artery disease Atherosclerosis 2001; 156: 417-424
23. Ault KA; Cannon CP; Mitchell J; McCahan J; Tracy RP; Novotny WF; Reimann JD; Braunwald E Platelet activation in patients after an acute coronary syndrome: Results from the TIMI-12 trial Journal of the American College of Cardiology 1999; 33: 634-639
24. Itoh T, Nakai K, Ono M, Hiramori K Can the risk for acute cardiac events in acute coronary syndrome be indicated by platelet membrane activation marker P-selectin? Coronary Artery Disease 1995; 6: 645-650
25. Soeki T, Tamura Y, Shinohara H, Sakabe K, Onose Y, Fukuda N Increased soluble platelet/endothelial cell adhesion molecule-1 in the early stages of acute coronary syndromes International Journal of Cardiology 2003; 90: 261-268