Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes

Abstract

BACKGROUND.

Patients with cancer who have thrombocytopenia may experience acute coronary syndromes (ACS), and the use of aspirin (ASA) poses an increased risk of bleeding. The purpose of this study was to test the hypothesis that the benefit of ASA therapy in the treatment of ACS would extend to cancer patients with thrombocytopenia and outweigh the risks of severe bleeding.

METHODS.

The records of all cancer patients diagnosed with an ACS in 2001 and referred for cardiology consultation were reviewed. Patients were divided into 2 groups on the basis of platelet count, >100 cells k/μL and ≤100 cells k/μL. Data were collected on the use of ASA therapy, bleeding complications, and survival rates. The authors assessed group differences by using the Wilcoxon rank sum test or 2-tailed Fisher exact test, as appropriate. Univariate and multivariate logistic regression models were used to assess factors potentially associated with 7-day survival.

RESULTS.

In cancer patients with ACS and thrombocytopenia, those who did not receive ASA had a 7-day survival rate of 6% compared with 90% in those who did receive ASA (P < .0001). There were no severe bleeding complications. Patients with a platelet count (>100 cells k/μL) who received ASA had a 7-day survival rate of 88% compared with 45% in those who did not receive ASA (P = .0096).

CONCLUSIONS.

Therapy with ASA was associated with a significantly improved 7-day survival after ACS in cancer patients, with or without thrombocytopenia, and not associated with more severe bleeding. Cancer 2007;109:621–627. © 2006 American Cancer Society.

The clinical presentation of an acute coronary syndrome (ACS), defined as unstable angina or acute myocardial infarction, in cancer patients may be similar to that observed in the general population; however, significant controversies exist about how these patients are treated, especially when thrombocytopenia is also present. Cancer survivors are at increased risk of developing coronary artery disease partly as a result of treatment but also due to prolonged survival.1, 2 Acute coronary syndrome (ACS) is known to occur when there is a combination of atherosclerotic plaques and superimposed thrombosis, and it may be precipitated by inflammation, infection, or rupture of vulnerable plaques.3 Cancer induces a prothrombotic state by various mechanisms, including platelet activation and aggregation, as well as an increase in procoagulant factors.4 Current guidelines of the American Heart Association/American College of Cardiology recommend aspirin (ASA) therapy in all cases of ACS.3 An exception and relative contraindication to such therapy may be thrombocytopenia. The guidelines for ACS were developed for patients with a normal platelet count, and in all major clinical trials of antithrombotic therapy and ACS, patients with cancer have generally been excluded. Therefore, no specific clinical guidelines exist for treating ACS in patients with cancer, with or without thrombocytopenia.

One clinical trial suggested that patients with ACS and thrombocytopenia have an increased incidence of bleeding and ischemic events compared with patients with ACS and a normal platelet count.4 Nevertheless, despite increased incidence of bleeding complications with antiplatelet therapy in these trials, the use of aspirin when compared with placebo consistently resulted in better overall clinical outcomes. It is particularly noteworthy that thrombocytopenia in these studies was usually caused by anticoagulation therapy and was not related to chemotherapy or bone marrow suppression. Yet another complicating factor in cancer treatment is the issue of hypercoagulability. Clinical thrombosis is estimated to occur in up to 15% of patients,6 and this hypercoagulable state is thought to be caused by substances secreted by tumor cells that may activate different aspects of the coagulation pathway.5 Iatrogenic devices and indwelling intravenous catheters, as well as the administration of heparin flushes, can also predispose patients to thrombosis and heparin-induced thrombocytopenia. Approximately 10% of patients with cancer have thrombocytopenia, defined as a platelet count of ≤100 cells k/μL.6 This can be caused by bone marrow infiltration, chemotherapy side effects, platelet sequestration in the spleen, or increased peripheral destruction that occurs in cases of severe sepsis, disseminated intravascular coagulation, and hemolytic uremic syndrome with thrombotic thrombocytopenic purpura. Thrombocytopenia and a propensity for increased thrombus formation coexist in several clinical syndromes, including hemolytic uremic syndrome with thrombotic thrombocytopenic purpura,7 antiphospholipid antibody syndrome,8 pregnancy-induced thrombocytopenia, and May-Hegglin anomaly.9 The mechanisms underlying thrombocytopenia and increased thrombus formation are not known; although, the hypercoagulable state of affected patients could be secondary to compensatory increases in platelet size and activation when patient platelet counts decrease. Several case reports have indicated the effectiveness of ASA in such patients.6–8 In some cases, treatment with ASA actually resulted in an increase in platelet count.9

Given these considerations, we hypothesized that the benefit of therapy with ASA for ACS would extend to patients with cancer who have thrombocytopenia secondary to chemotherapy or bone marrow suppression and that any risk of bleeding would be more than acceptable by clinical benefit. Conversely, we hypothesized that withholding ASA in cancer patients with ACS would be harmful. Thus, to investigate these hypotheses, we conducted a retrospective analysis of patients with cancer and ACS with and without thrombocytopenia, who were admitted to the University of Texas M. D. Anderson Cancer Center over a 1-year period. We evaluated the effect of treatment with ASA on survival and the incidence of bleeding.

MATERIALS AND METHODS

Patients

Medical records of all patients with a diagnosis of ACS who were referred and treated at M. D. Anderson Cancer Center in the year 2001 were reviewed by a single observer. The diagnosis of ACS in these patients was determined on the basis of the presence of any 2 criteria as follows: (1 chest pain, (2 characteristic electrocardiogram (ECG) changes of ACS, and (3 a characteristic rise in cardiac enzymes. Elevated cardiac enzyme level was defined as creatine kinase levels more than twice the normal limit, creatine kinase isoenzyme levels >10% above the normal limit, and troponin I levels >1.4 ng/mL. Patients with heparin-induced thrombocytopenia were excluded from study. The current study was approved by the M. D. Anderson Cancer Center Institutional Review Board. Patients were divided into 2 groups according to their platelet count at the time of ACS diagnosis as follows: those with a normal platelet count (>100 cell k/μL) and those with thrombocytopenia (platelet count ≤100 cells k/μL). We assessed the following characteristics in each patient, the underlying cancer diagnosis, which was classified as solid tumor or hematologic; risk factors for CAD, including age, sex, previous history of CAD, smoking history, hypertension, family history, and presence of diabetes mellitus; use of ASA and β-blockers; and the 7-day survival rate in both groups according to whether ASA therapy was instituted. In addition, we analyzed the mean hemoglobin level at the onset of ACS, the incidence of bleeding, and the need for blood and platelet transfusions in each group. For the purpose of the current study, major bleeding complications in relation to ASA were defined as a decrease in hemoglobin level of >2 gm/dL from baseline, any overt genitourinary or gastrointestinal bleeding, any intracranial bleeding, any need for blood transfusion, and internal bleeding in any organ. In view of a potential for bleeding complications, these patients were followed meticulously for any signs of bleeding.

Statistical Analyses

We assessed platelet level group differences using the Fisher exact test and Wilcoxon rank sums test as appropriate. Univariate and multivariate logistic regression models were used to examine factors potentially associated with 7-day survival. Independent variables included demographic variables (age, sex), risk factors for developing coronary artery disease (history of coronary artery disease, diabetes, hypertension, smoking), severity of myocardial infarction (presence of Q-waves, ST segment elevation, troponin level, creatine kinase–MB fraction [CK–MB], initial ejection fraction), treatment factors (use of aspirin, use of β-blockers, hemoglobin level, platelet count, platelet transfusion 1 week before or 1 week after myocardial infarction, packed red blood cell transfusion, bleeding), and type of tumor. Factors associated with 7-day survival at P < .10 were considered in multivariate modeling. The final model was derived by using a forward selection procedure. P-values of < .05 were considered statistically significant. Analyses were performed with SAS for Windows (release 9.1; SAS Institute Inc., Cary, NC).

RESULTS

A total of 70 patients were identified with ACS at M. D. Anderson in 2001; of these patients, 43 (61%) had normal platelet counts (>100 cells k/μL), and 27 (39%) were thombocytopenic (platelet count ≤100 cells k/μL). The baseline risk factors and demographics were similar in both groups (Table 1), except those with normal platelets were more likely to have a solid tumor (P = .0001). In the normal platelet group, the median platelet count was 225,000 (range, 121,000 to 498,000). In the thrombocytopenic group, the median platelet count was 32,000 (range, 4,000 to 100,000) (Table 2). Additionally, patients with normal platelet counts had a significantly higher hemoglobin level (median, 10.90) than did patients with low platelets (median, 8.80) (P < .0002) and a lower initial heart rate (92 vs 112, P = .02) upon presentation. There was no significant difference in systolic blood pressure upon presentation between the groups. In addition, there was nonsignificant trend toward lower left ventricular ejection fraction (P = .0529) in the normal platelet group (Table 2).

Table 1. Demographics of Cancer Patients With Acute Myocardial Infarction

Characteristics	Total	>100 k/μL	≤100 k/μL	*P
	N = 70	N = 43	N = 27
	No. (%)	No. (%)	No. (%)
All data are presented as number and percentage, except age, which is mean plus or minus the standard deviation, SD. Comparisons were not significant except as indicated.
Women	23 (33)	15 (35)	8 (30)
Men	47 (67)	28 (65)	19 (70)
Age, mean ± SD	67 (10)	68 (10)	64 (9)
Hypertension	39 (57)	25 (61)	14 (52)
Diabetes mellitus	18 (26)	11 (27)	7 (26)
Hyperlipidemia	38 (54)	23 (53)	15 (56)
Smoking	46 (66)	28 (65)	18 (67)
Family history	22 (31)	15 (35)	7 (26)
Coronary artery disease	20 (29)	13 (32)	7 (26)
Cancer diagnosis
Solid	54 (77)	40 (93)	14 (52)	.0001
Hematologic	16 (23)	3 (7)	13 (48)

Table 2. Clinical Parameters of Cancer Patients Presenting With Acute Myocardial Infarction

Characteristics	Total	>100 k/μL	≤100 k/μL	P
	N = 70	N = 43	N = 27
	No. (%)	No. (%)	No. (%)
CK-MB indicates creatinine kinase-MB fraction. All data are presented as median (minimum, maximum), except presence of ST segment elevation, which are expressed as number and percentage, No. (%). * P-values (only significant values shown) are from Fisher exact test. † P-value from Wilcoxon rank sums test.
Heart rate, beats/min on admission		92 (60, 180)	112 (68, 150)	.02*
Systolic blood pressure, mmHg		118 (70, 187)	115 (60, 160)
Hemoglobin, gm/dL	10 (6, 16)	11 (6, 16)	9 (6, 13)	.0002†
Platelet count, cells k/μL	169 (4, 498)	225 (121, 498)	32 (4, 100)	<.0001*
ST segment elevation	17 (24)	9 (21)	8 (30)
Troponin I, ng/mL	4 (0, 77)	3 (0, 48)	5 (2, 77)
CK-MB, ng/mL	12 (1, 253)	10 (1, 253)	18 (2, 110)
% Left ventricular ejection fraction	50 (20, 70)	48 (20, 70)	55 (23, 68)

The management of ACS differed by patient group. Fewer patients in the thrombocytopenia group received treatment with ASA and β-blockers than did patients in the normal platelet count group. Thirty-seven percent (n = 10) of patients with thrombocytopenia received ASA, compared with 74% (n = 32) of patients with a normal platelet count (P = .0027), Figure 1. Similarly, 41% (n = 11) of patients with thrombocytopenia received β-blockers compared with 74% (n = 32) of patients with a normal platelet count (P = .0062), Figure 2.

Figure 1. Percentage survival of AMI patients who were given aspirin. ASA indicates aspirin therapy; AMI, acute myocardial infarction.

Figure 2. Percentage survival of cancer patients with AMI who were given β-blockers. β-blocker indicates β-blocker therapy; AMI, acute myocardial infarction.

The 7-day survival rate was significantly higher in the normal platelet count group (77%) than in the thrombocytopenia group (37%), P = .0012. In both groups, the survival of patients who received ASA was significantly higher than that in patients who did not receive ASA. In the thrombocytopenia group, the overall 7-day survival in patients who received ASA was 90% compared with 6% in those who did not receive ASA (P < .0001). Likewise, in the group with a normal platelet count, the overall survival in patients who received ASA was 88% compared with 45% in those patients who did not receive ASA (P = .0096) (Figure 1). There were parallel findings for those patients in either group who were treated with β-blockers. In those with a normal platelet count, 29 to 32 (91%) patients survived >7 days when treated with β-blockers, whereas only 4 of 11 (36%) survived when not treated, P = .001 (Figure 2). In the thrombocytopenic group, 8 of 11 (73%) patients survived >7 days when treated with β-blockers whereas only 2 of 16 (13%) survived when they were not treated (P < .001) (Figure 2).

In univariate logistic regression analysis, higher risk of death was associated with no use of ASA (odds ratio [OR] = 27.13; 95% confidence interval [CI expressed as upper limit, lower limit]: 7.40, 99.44; P < .0001), no use of β-blockers (OR = 21.58; 95% CI: 6.17, 75.48; P < .0001), hematologic malignancy (OR = 3.63; 95% CI: 1.13, 11.61), lower platelet count (OR = 0.994; 95% CI: 0.990, 0.999; P = .0086), receipt of platelets 1 week before myocardial infarction (OR = 12.06; 95% CI: 2.39, 60.93; P = .0026), lower hemoglobin level (OR = 0.733; 95% CI: 0.56, 0.95; P = .0197), and a strong trend in those with ST segment elevation (OR = 3.43: 95% CI: 1.10,10.70; P = .054). These variables, along with other variables associated with 7-day survival at P < .10 (receipt of blood transfusion during week after myocardial infarction and receipt of platelets during week after myocardial infarction), were considered for multivariate analysis by using a forward selection procedure. Multivariate logistic regression analysis revealed that no ASA use (OR = 18.44; 95% CI: 2.87, 118.60; P = .0021), no β-blocker use (OR = 31.65; 95% CI: 2.80, 357.45; P = .0052), ST segment elevation (OR = 17.24; 95% CI: 1.84, 161.67; P = .0127), and receipt of blood transfusion during the week after myocardial infarction (OR = 12.06; 95% CI: 1.03, 141.14; P = .0473) were significant risk factors for death while controlling for platelet level (Table 3).

Table 3. Univariate and Multivariate Analysis of Clinical Parameters Associated With 7-Day Mortality

Label	Value	Total	Survived 7 days		Univariate			Multivariate-reduced model
			No	Yes	OR	95% CI	P	OR	95% CI	P
			No. (%)	No. (%)							Lower, upper	Lower, upper
ACS indicates acute coronary syndrome; CK-MB, creatine kinase–MB fraction blood test.
Platelet count		70			0.994	0.99, 0.999	.0086	1.00	0.99, 1.00	.5415
Patient sex	women	23	12 (52)	11 (48)	2.327	0.837, 6.47	.11
	men	47	15 (32)	32 (68)	1.000
Coronary artery disease	no	48	20 (42)	28 (58)	1.667	0.546, 5.084	.37
	yes	20	6 (30)	14 (70)	1.000
Diabetes mellitus	no	50	20 (40)	30 (60)	1.333	0.43, 4.134	.62
	yes	18	6 (33)	12 (67)	1.000
Hypertension	yes	39	15 (38)	24 (62)	1.023	0.38, 2.751	.96
	no	29	11 (38)	18 (62)	1.000
Cancer diagnosis	hematologic	16	10 (63)	6 (38)	3.627	1.133, 11.61	.03
	solid	54	17 (31)	37 (69)	1.000
History of smoking	no	24	12 (50)	12 (50)	2.067	0.753, 5.675	.16
	yes	46	15 (33)	31 (67)	1.000
ASA treatment	no	28	22 (79)	6 (21)	27.13	7.403, 99.44	<.0001	18.44	2.87, 118.60	.0021
	yes	42	5 (12)	37 (88)	1.000
Beta-blocker treatment	no	27	21 (78)	6 (22)	21.58	6.172, 75.48	<.0001	31.65	2.80, 357.45	.0052
	yes	43	6 (14)	37 (86)	1.000
Bleeding	yes	12	6 (50)	6 (50)	1.762	0.504, 6.161	.38
	no	58	21 (36)	37 (64)	1.000
Platelets 1 wk before ACS	yes	12	10 (83)	2 (17)	12.06	2.386, 60.93	<.0026
	no	58	17 (29)	41 (71)	1.000
Platelets 1 wk after ACS	yes	7	5 (71)	2 (29)	4.659	0.835, 26.01	.08
	no	63	22 (35)	41 (65)	1.000
ST segment elevation	yes	17	10 (59)	7 (41)	3.43	1.10, 10.70	.05	17.24	1.84, 161.67	.0127
	no	53	17 (32)	3 (68)	1.000
Blood transfusions Week 1	yes	27	14 (52)	13 (48)	2.485	0.917, 6.733	.07	12.06	1.03, 141.14	.0473
	no	43	13 (30)	30 (70)	1.000
Hemoglobin level		70			0.733	0.564, 0.952	.0197
CK-MB		70			1.002	0.99, 1.014	.73
Troponin I level		69			1.010	0.977, 1.044	.55
Initial ejection fraction		57			1.008	0.971, 1.046	.68

No incidences of acute major gastrointestinal bleeding, intracranial hemorrhage, or fatal bleed occurred. Minor bleeding occurred in 17% (n = 12) of the patients and was not significantly associated with ASA use (P = .80). Bleeding occurred more frequently among patients who had thrombocytopenia (P = .0073), but the incidence of minor bleeding among patients with thrombocytopenia did not differ significantly by ASA use (P = .22) (Figure 3). In patients with thrombocytopenia who received ASA, there were 5 cases of minor bleeding (hematoma at the placement site of central line (n = 2), hematuria and occult blood in the stool (n = 1), or ecchymosis (n = 2). In patients with thrombocytopenia who did not receive ASA, minor bleeding occurred in 4 patients (epistaxis (n = 1), hematoma at the placement site of a central line (n = 1), melena and ecchymosis (n = 1), and melena alone (n = 1). In the thrombocytopenia group, a total of 3 patients who received ASA underwent transfusion of packed red blood cells for anemia. Twelve of the patients in the thrombocytopenia group received a platelet transfusion during the week before their index ACS event. None of the patients with a normal platelet count at admission received a platelet transfusion in the weeks before or after their index ACS event.

Figure 3. ASA use and bleeding complications in cancer patients with AMI. ASA indicates aspirin therapy; NL PLT, normal platelet group; Low PLT, low platelet group.

DISCUSSION

Our data suggest that among patients with cancer who develop an ACS, the presence of thrombocytopenia is associated with a worse outcome. However, ASA therapy in these patients may influence outcome and is associated with improved 7-day survival without a significant increase in bleeding complications. To our knowledge, the current report is the first to describe the risk-benefit profile of ASA therapy in this high-risk patient population. These results apply to those patients with elevated troponins chest pain and dynamic electrocardiographic changes, a population considered to be at increase risk for serious complications including death.

The reason for this “platelet paradox” of coronary thrombosis in thrombocytopenic patients is unclear. Various factors including underlying coronary disease, hypercoagulability, or, perhaps, adverse effects resulting from cancer therapy that disturb the coagulation cascade may predispose these patients to thrombotic complications. Platelet activation in cancer is mediated by a variety of mechanisms, ranging from increased expression of platelet adhesion molecules to direct platelet activation by contact with molecules on the surface of the tumor cell membrane.10 Compared with healthy controls, patients with cancer have higher levels of fibrinogen, von Willebrand factor, and soluble P-selectin (a marker of increased platelet activation).11 When compared with healthy women, patients with breast carcinoma have increased platelet adhesion to fibrinogen.12 Furthermore, platelets from women with metastasis have increased adhesion compared with those women who have no metastasis.12 Another prothrombotic mechanism in thrombocytopenia includes increased release of reticulated platelets,13 which are likely to be more active than mature platelets, and it is speculated that this release may precipitate thrombosis of a coronary vessel under conditions associated with a plaque rupture.

In the current study, patients with thrombocytopenia had a lower 7-day survival rate than did patients in the normal platelet count group, despite their similar clinical risk factors, cardiac enzyme elevation, and overall left ventricular ejection fraction. These data suggest that the lower survival rate in patients with thrombocytopenia cannot be explained only by more extensive myocardial necrosis. The thrombocytopenia group did have a lower hemoglobin level and had required more platelet transfusions before the index event (Tables 1, 2, and 3); thus, the hematologic disturbance, including activation of platelets, may be higher in this group, and their ability to respond further may be diminished compared with the normal platelet group.

Coronary event intervention by use of aspirin, clopidogrel, and heparin has been occasionally reported as a treatment for patients with thrombocytopenia.14 Despite thrombocytopenia and treatment with both aspirin and clopidogrel, thrombotic stent occlusion has been reported,14 thus suggesting that patients with malignancy, although thrombocytopenic, are predisposed to thrombotic vascular complications. The fear of bleeding complications might have resulted in a lower administration of ASA to thrombocytopenic patients. Interestingly, the thrombocytopenic patients, despite having adequate blood pressure and heart rate, were also less likely to receive β-blockers. Although our data do not allow us to explain this practice pattern, it may be that physician desire to avoid side effects might have contributed to the reported low administration rate of both ASA and β-blockers. Such perceptions might simply have been more prevalent in the management of cancer patients with ACS, and these perceptions may demonstrate general ineffectiveness in translating results from important cardiovascular clinical trials into everyday clinical practice.

Our data does not provide any insight into the importance of platelet function in ACS and thrombocytopenia. This information will be difficult to obtain, because none of the currently available tests of platelet function can reliably assess it in the setting of a platelet count <50 cells k/μL. However, thromboelastography may be able to assess platelet function under these circumstances.14

This study has all the limitations intrinsic to a retrospective study and a small sample size. The number of variables that could be included in the multivariate analysis limited the calculation of precise risk estimates. However, all data were collected meticulously, and the treatment practice pattern reflected the general management of ACS in a cancer population. Ideally, a large randomized study of ACS in cancer patients should be performed, but fear of bleeding complications probably precludes such a study. Previous data from the National Registry of Myocardial Infarction suggest that ASA is underused in patients with ACS.15

On the basis of this study, clinicians should consider using ASA in cancer patients with ACS and thrombocytopenia. However, in every case, the risk should be weighed against the benefit, because, despite the low incidence of bleeding complication in our study, the potential for bleeding in patients with thrombocytopenia is high.

Acknowledgements

We thank collaborators Dr. Charles Koller, Dr. Ann Tong, Myrshia Woods, Mary T. Vooletich, Brett Simchowitz, and Amber Reece. We also thank Dr. Elihu H. Estey, Dr. Saroj Vadhan-Raj, and Dr. James J. Ferguson for critical review of this manuscript and Kawana Guillory and Amy Chiu for administrative support