Abstract
Background:
Data on the association of baseline thrombocytopenia (TP) with long-term outcomes of patients with acute ST-segment elevated myocardial infarction (STEMI) are still limited.
Methods and Results:
A total of 16,957 consecutive cases of patients with STEMI from multiple centers that participated in the China Acute Myocardial Infarction (CAMI) registry were included in this study. Two-year clinical outcomes were evaluated between patients with TP and those with a normal platelet count (PLT). Cases coexisting with baseline TP accounted for 2.1%. The rates of 2-year all-cause death (21.4% and 11.4%, P<0.001) and major adverse cardiovascular and cerebrovascular events (MACCE) (23.6% and 13.9%, P<0.001) were significantly higher in cases with TP, compared with the normal PLT group. After multivariate adjustment, compared with the control, cases with TP were not independently associated with 2-year all-cause death (HR: 1.21; 95% CI: 0.96–1.52; P=0.110) and MACCE (HR: 1.18; 95% CI: 0.95–1.47; P=0.132). After propensity score matching (PSM), the rates of 2-year all-cause death and MACCE were similar between the 2 groups (20.7% and 17.9%, P=0.317; 23.0% and 19.9%, P=0.288). Multivariable adjustment after PSM showed baseline TP was not independently associated with all-cause death (HR: 1.21; 95% CI: 0.88–1.67; P=0.240) and MACCE (HR: 1.21; 95% CI: 0.89–1.63; P=0.226).
Conclusions:
Patients with STEMI and baseline TP had higher rates of all-cause death and MACCE; however, baseline TP was not independently associated with 2-year adverse outcomes in patients with STEMI after multivariate adjustment and controlling for baseline differences.
In recent large-sample studies, approximately 5.7% of patients with acute coronary syndrome (ACS), 3.3% of patients with acute myocardial infarction (AMI) and 2.2–4.2% of patients with acute ST-segment elevated myocardial infarction (STEMI) were diagnosed with a coexistence with baseline thrombocytopenia (TP).1–4
Studies have also suggested that baseline TP is an independent risk factor for the in-hospital and long-term prognosis of patients with ACS.1,2,4
Dual antiplatelet therapy (DAPT) is recommended for AMI patients, but clinical management is difficult in those with TP.3
There is still limited evidence and no clear recommendation in current guidelines for this interdisciplinary population.5–7
In our previous study of the China Acute Myocardial Infarction (CAMI) registry, we found an increased risk of in-hospital death in patients with STEMI and TP.3
Therefore, the following 2-year prognosis study was conducted to further analyze patients with STEMI and TP in order to provide more data for an antithrombotic therapy strategy and provide a prognostic assessment of this particular population.
Methods
Data Collection
The CAMI registry is a prospective, nationwide, multicenter observational study of patients admitted with AMI to hospitals in China. Details of this registry, including data management and quality control, have been previously published.8
The registry involves 3 levels of hospitals (prefectural, provincial, and country level) representing typical Chinese governmental and administrative models. The hospitals are allocated in provinces and municipalities throughout mainland China (except for Hong Kong and Macau), and represent not only the levels of health care, but also the geographical region hierarchy. Each institution consecutively enrolled patients who were considered eligible if they presented with an ischemic symptom for 7 days and had a final primary diagnosis of AMI (either STEMI or non-STEMI). Data were entered into a fixed table, and included a standardized set of variables and definitions, under rigorous data quality control. Baseline demographics, procedural or operative characteristics, and outcome data were recorded in a database by independent research personnel for all patients who provided written informed consent for participation and clinical follow up. This study was registered with ClinicalTrials.gov (NCT01874691) and was approved by the institutional review board of each participating hospital.
Study Population
A total of 28,070 patients with AMI from 108 hospitals were enrolled in the CAMI registry from 1 January 2013 to 30 September 2014. A normal platelet count is defined as 100–300×109/L, based on platelet number distribution and domestic criteria.3,9,10
The following patients were excluded: (1) patients with non-STEMI or missing a diagnosis at admission; (2) patients undergoing intra-aortic balloon pumping (IABP) during emergency treatment, an intervention procedure, or admission (we excluded these patients because IABP leads to acquired TP); (3) patients with missing platelet count data; and (4) patients with a platelet count >300×109/L (we excluded these patients because thrombocythemia can affect the prognosis of patients with ACS and distinguishing the causes of thrombocytosis is challenging11). A total of 16,957 patients diagnosed with STEMI were finally included in this study (Figure 1). In this selected cohort, the first and third quartiles were evenly distributed at approximately 200×109/L (Figure 2). The median and average platelet numbers were stable in both the total cohort and the selected analyzed cohort. Baseline TP was defined as a platelet count <100×109/L on admission. Patients in the TP group were classified into those with mild TP and moderate/severe TP according to platelet counts of 50–100×109/L and 0–50×109/L, respectively.9,10
Follow-up visits are planned at 30 days, 6, 12, 18, and 24 months. The events (including death, cardiovascular events, bleeding, and so on), medications, the reasons for medication discontinuation, and cost of medication will be reviewed and collected either in person at a clinic visit or by telephone call. The clinical events must be validated by source documents.8
The primary outcome was all-cause death and major adverse cardiovascular and cerebrovascular events (MACCE) (including all-cause death, recurrent myocardial infarction (MI), and ischemic stroke). Seeing a doctor or readmission due to heart failure (HF) meant newly occurring or aggravated HF, which was diagnosed by clinical manifestations including cardiac dyspnea, pink frothy sputum, and crackles, as well as a supporting examination such as an echocardiogram, X-ray or N-terminal pro-brain natriuretic peptide. Bleeding events, which included hemorrhagic stroke, were defined according to criteria established by the Bleeding Academic Research Consortium. Severe bleeding was defined according to criteria established by the Bleeding Academic Research Consortium (BARC), excluding BARC 0, 1 and 2 types.12
Statistical Analysis
Continuous normally distributed variables were expressed as mean values (standard deviation) and compared using the Student’s 2-tailed unpaired t-test. Continuous non-normally distributed variables were expressed as median values (interquartile range) and were analyzed using the Wilcoxon rank test. Categorical variables were shown as counts (percentages) and compared using the chi-squared test or Fisher’s exact test. The multivariate COX regression model was built to evaluate the association between TP comorbidities and 2-year outcomes. Variables included in the multivariable model were either statistically significant in univariate analysis (P<0.05) or clinically critical. These results were reported as hazard ratios (HRs) with 95% confidence intervals (95% CIs). Variables included in the multivariate COX regression model before propensity score matching (PSM) were: age, gender, body mass index (BMI), smoking status, hyperlipidemia, previous percutaneous coronary intervention (PCI), white blood cell (WBC) count, hemoglobin, Grace score, aspirin, IIb/IIIa receptor antagonists, β-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs). PSM using nearest neighbor matching with a 1 : 1 ratio (caliper value: 0.0007) was applied to control for baseline differences. Variables used in PSM were: age, gender, BMI, smoking status, hyperlipidemia, previous PCI, history of tumor, WBC count, hemoglobin, Grace score, serum creatinine, aspirin, IIb/IIIa receptor antagonists, β-blockers and ACEIs/ARBs. All analyses were 2-sided, and statistical significance was defined as P<0.05. Statistical analysis was performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).
Results
Baseline Characteristics
A total of 364 patients had baseline TP, accounting for 2.1% of the entire cohort. Overall, patients with STEMI and TP presented with older age, and more comorbidities, such as a higher rate of chronic obstructive pulmonary disease (COPD) and tumor history, lower level of hemoglobin, higher level of serum creatinine, and a higher Grace score. Aspirin and IIb/IIIa receptor antagonist were applied significantly less frequently in patients with TP than in those with a normal platelet count. The use of a P2Y12 receptor inhibitor showed no difference between the 2 groups. Other secondary prevention drugs, including β-blockers and ACEIs/ARBs, were used less often in patients with TP than in those with a normal platelet count (Table 1).
Table 1.
Baseline Characteristics and Medications Taken Between Patients With TP and Patients With a Normal Platelet Count Before and After PSM
| |
Before PSM |
After PSM |
Patients with
TP (n=364) |
Patients with a
normal platelet
count (n=16,593) |
P value |
Patients with
TP (n=352) |
Patients with a
normal platelet
count (n=352) |
P value |
| Demographic characteristics |
| Age, years |
66.5±13.8 |
61.2±14.2 |
<0.001 |
66.4±13.7 |
66.3±14.2 |
0.889 |
| Male gender, % |
289 (79.4) |
12,879 (77.6) |
0.416 |
278 (79.0) |
287 (81.5) |
0.401 |
| BMI, kg/m2 |
23.5±2.9 |
24.1±2.9 |
<0.001 |
23.6±2.9 |
23.6±2.7 |
0.919 |
| Thrombosis risks and coexisting conditions, % |
| Current smoker |
139 (38.2) |
7,950 (47.9) |
0.002 |
137 (38.9) |
140 (39.8) |
0.904 |
| Family history of premature CAD |
7 (1.9) |
599 (3.6) |
0.173 |
7 (2.0) |
8 (2.3) |
0.284 |
| Hypertension |
170 (46.7) |
7,944 (47.9) |
0.906 |
166 (47.2) |
163 (46.3) |
0.846 |
| Hyperlipidemia |
14 (3.8) |
1,115 (6.7) |
0.020 |
14 (4.0) |
13 (3.7) |
0.954 |
| DM |
70 (19.2) |
2,971 (17.9) |
0.517 |
70 (19.9) |
63 (17.9) |
0.391 |
| Previous MI |
15 (4.1) |
992 (6.0) |
0.175 |
15 (4.3) |
22 (6.3) |
0.355 |
| Previous PCI |
10 (2.7) |
499 (3.0) |
0.004 |
10 (2.8) |
14 (4.0) |
0.833 |
| Previous HF |
8 (2.2) |
217 (1.3) |
0.267 |
7 (2.0) |
6 (1.7) |
0.955 |
| Stroke |
32 (8.8) |
1,445 (8.7) |
0.182 |
30 (8.5) |
36 (10.2) |
0.853 |
| CRF |
3 (0.8) |
132 (0.8) |
0.794 |
3 (0.9) |
7 (2.0) |
0.318 |
| COPD |
11 (3.0) |
282 (1.7) |
0.040 |
11 (3.1) |
14 (4.0) |
0.757 |
| Rheumatic diseases |
2 (0.5) |
121 (0.7) |
0.039 |
2 (0.6) |
1 (0.3) |
0.924 |
| History of tumor |
10 (2.7) |
187 (1.1) |
0.001 |
8 (2.3) |
7 (2.0) |
0.785 |
| History of liver disease |
6 (1.7) |
169 (1.0) |
0.088 |
6 (1.7) |
4 (1.1) |
0.494 |
| Physical and laboratory examination |
| HR at admission, beats/min |
76.5±21.3 |
77.2±18.2 |
0.563 |
76.7±21.4 |
77.9±18.1 |
0.414 |
| SBP at admission, mmHg |
122.4±26.3 |
127.4±25.1 |
<0.001 |
122.8±26.2 |
121.9±25.2 |
0.637 |
| WBC count, ×109/L |
9.15±5.16 |
10.36±3.54 |
<0.001 |
9.29±5.17 |
9.34±3.20 |
0.847 |
| Serum creatinine, mg/dL |
1.11±0.74 |
0.95±1.20 |
<0.001 |
1.10±0.74 |
1.05±0.84 |
0.323 |
| Hemoglobin, g/L |
128.1±27.8 |
137.9±20.4 |
<0.001 |
129.4±26.8 |
129.9±22.1 |
0.804 |
| Treatment strategy |
| Grace Score |
163.0±38.0 |
147.4±34.6 |
<0.001 |
162.1±37.5 |
164.7±37.8 |
0.246 |
| Emergency revascularization, % |
86 (23.6) |
4,282 (25.8) |
0.342 |
86 (24.4) |
104 (29.5) |
0.123 |
| Medication during hospitalization, % |
| Aspirin |
332 (91.2) |
16,060 (96.8) |
<0.001 |
327 (92.9) |
320 (90.9) |
0.759 |
| P2Y12 receptor inhibitor |
|
|
0.085 |
|
|
0.917 |
| Clopidogrel |
355 (97.5) |
16,133 (97.2) |
|
345 (98.0) |
342 (97.2) |
|
| Ticagrelor |
5 (1.4) |
394 (2.4) |
|
5 (1.4) |
8 (2.3) |
|
| Prasugrel |
0 (0.0) |
14 (0.1) |
|
0 (0.0) |
1 (0.3) |
|
| LMWH or fondaparinux |
348 (95.6) |
16,031 (96.6) |
0.314 |
336 (95.5) |
345 (98.0) |
0.093 |
| IIb/IIIa receptor antagonist |
89 (24.5) |
5,743 (34.6) |
<0.001 |
87 (24.7) |
89 (25.3) |
0.853 |
| OAC |
5 (1.4) |
236 (1.4) |
0.678 |
5 (1.4) |
8 (2.3) |
0.639 |
| Statin |
347 (95.3) |
16,171 (97.5) |
0.074 |
336 (95.5) |
341 (96.9) |
0.699 |
| β-blocker |
225 (61.8) |
11,528 (69.5) |
0.004 |
222 (63.1) |
220 (62.5) |
0.644 |
| Calcium antagonist |
40 (11.0) |
2,036 (12.3) |
0.618 |
40 (11.4) |
41 (11.6) |
0.798 |
| ACEI/ARB |
169 (46.4) |
9,708 (58.5) |
<0.001 |
169 (48.0) |
168 (47.7) |
0.973 |
| AAD |
36 (9.9) |
1,759 (10.6) |
0.660 |
33 (9.4) |
32 (9.1) |
0.898 |
| Aldosterone antagonist |
95 (26.1) |
4,519 (27.2) |
0.629 |
93 (26.4) |
118 (33.5) |
0.039 |
| Diuretics |
129 (35.4) |
5,615 (33.8) |
0.525 |
124 (35.2) |
142 (40.3) |
0.157 |
| Acid inhibitor |
261 (71.7) |
11,834 (71.3) |
0.873 |
254 (72.2) |
261 (74.1) |
0.553 |
Data are expressed as mean±standard deviation; or counts (percentage). AAD, antiarrhythmic drug; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; DM, diabetes mellitus; HF, heart failure; HR, heart rate; LMWH, low molecular weight heparin; MI, myocardial infarction; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; PSM, propensity score matching; SBP, systolic blood pressure; TP, thrombocytopenia; WBC, white blood cell. Variables used in PSM were: age, gender, BMI, smoking status, hyperlipidemia, previous PCI, history of tumor, WBC count, hemoglobin, Grace score, serum creatinine, aspirin, IIb/IIIa receptor antagonists, β-blockers and ACEIs/ARBs.
The incidence of all-cause death was significantly higher in patients with TP than in those with a normal platelet count (21.4% and 11.4%, P<0.001). Accordingly, the MACCE risk in patients with TP was significantly higher than that in patients with a normal platelet count (23.6% and 13.9%, P<0.001). The rates of recurrent MI, seeing a doctor or readmission due to HF, revascularization (coronary artery bypass graft (CABG) or PCI), ischemic stroke, severe bleeding and readmission were all similar between the 2 groups (P>0.05) (Table 2). Kaplan-Meier survival curves revealed the consistent results (Figure 3A–C).
Table 2.
Two-Year Outcomes Between Patients With TP and Patients With a Normal Platelet Count Before and After PSM
| Events |
Before PSM |
After PSM |
Patients with
TP (n=364) |
Patients with a
normal platelet
count (n=16,593) |
P value |
Patients with
TP (n=352) |
Patients with a
normal platelet
count (n=352) |
P value |
| All-cause death |
78 (21.4) |
1,892 (11.4) |
<0.001 |
73 (20.7) |
63 (17.9) |
0.317 |
| MACCE |
86 (23.6) |
2,313 (13.9) |
<0.001 |
81 (23.0) |
70 (19.9) |
0.288 |
| Recurrent MI |
7 (1.9) |
394 (2.4) |
0.563 |
7 (2.0) |
5 (1.4) |
0.774 |
| Seeing a doctor or readmission due to HF |
16 (4.4) |
731 (4.4) |
0.993 |
14 (4.0) |
18 (5.1) |
0.585 |
| CABG or PCI |
20 (5.5) |
1,178 (7.1) |
0.220 |
20 (5.7) |
16 (4.5) |
0.618 |
| Ischemic stroke |
1 (0.3) |
76 (0.5) |
1.000 |
1 (0.3) |
3 (0.9) |
0.625 |
| Severe bleeding |
2 (0.5) |
163 (1.0) |
0.590 |
2 (0.6) |
5 (1.4) |
0.453 |
| Readmission |
42 (11.5) |
2,147 (12.9) |
0.423 |
39 (11.1) |
41 (11.6) |
0.808 |
Data are presented as n (%). CABG, coronary artery bypass graft; MACCE, major adverse cardiovascular and cerebrovascular event. Other abbreviations as in Table 1.
A univariate Cox regression model showed that coexisting with baseline TP was independently associated with all-cause death (HR: 1.98; 95% CI: 1.58–2.48; P<0.001) and MACCE (HR: 1.80; 95% CI: 1.45–2.23; P<0.001) compared with patients with a normal platelet count. After multivariate adjustment of possible confounders, baseline TP was not independently associated with all-cause death (HR: 1.21; 95% CI: 0.96–1.52; P=0.11), and MACCE (HR: 1.18; 95% CI: 0.95–1.47; P=0.132). And cases with baseline TP had no increased risk of other ischemic events, or severe bleeding (HR: 0.60; 95% CI: 0.15–2.41; P=0.467) (Table 3).
Table 3.
Multivariate Cox Regression Models Before and After PSM
| Events |
Before PSM |
After PSM |
| Hazard ratio (95% CI) |
P value |
Hazard ratio (95% CI) |
P value |
| All-cause death |
1.21 (0.96–1.52) |
0.110 |
1.21 (0.88–1.67) |
0.240 |
| MACCE |
1.18 (0.95–1.47) |
0.132 |
1.21 (0.89–1.63) |
0.226 |
| Recurrent MI |
0.86 (0.41–1.82) |
0.692 |
1.43 (0.46–4.50) |
0.539 |
| Seeing a doctor or readmission due to HF |
0.85 (0.52–1.40) |
0.524 |
0.83 (0.42–1.64) |
0.582 |
| CABG or PCI |
0.86 (0.55–1.34) |
0.493 |
1.27 (0.65–2.48) |
0.492 |
| Ischemic stroke |
0.50 (0.07–3.64) |
0.496 |
0.31 (0.03–3.02) |
0.312 |
| Severe bleeding |
0.60 (0.15–2.41) |
0.467 |
0.43 (0.08–2.31) |
0.325 |
| Readmission |
0.90 (0.66–1.22) |
0.491 |
1.00 (0.65–1.54) |
0.994 |
CI, confidence interval. Other abbreviations as in Tables 1,2. Included co-variables were as follows: (1) before PSM: age, gender, BMI, smoking status, hyperlipidemia, previous PCI, WBC count, hemoglobin, Grace score, aspirin, IIb/IIIa receptor antagonists, β-blockers and ACEIs/ARBs; and (2) after PSM: aldosterone antagonist.
Medication intake at the 2-year follow up showed that aspirin use was still significantly less in cases with TP than those with a normal platelet count (82.7% and 91.7%, P=0.015). The use of a P2Y12 receptor inhibitor and other secondary prevention drugs, including β-blockers, ACEIs/ARBs and statins, showed no difference between the 2 groups (Table 4).
Table 4.
Medication Use at 2-Year Follow up Between Patients With TP and Patients With a Normal Platelet Count Before and After PSM
| Medication, % |
Before PSM |
After PSM |
Patients with
TP (n=364) |
Patients with a
normal platelet
count (n=16,593) |
P value |
Patients with
TP (n=352) |
Patients with a
normal platelet
count (n=352) |
P value |
| Aspirin |
86/104 (82.7) |
6,132/6,686 (91.7) |
0.015 |
86/103 (83.5) |
118/134 (88.1) |
0.981 |
| P2Y12 receptor inhibitor |
25/103 (24.3) |
1,375/6,669 (20.6) |
0.716 |
23/102 (22.5) |
29/134 (21.6) |
0.985 |
| OAC |
0/104 (0.0) |
23/6,632 (0.3) |
1.000 |
0/103 (0.0) |
0/132 (0.0) |
0.801 |
| Statin |
88/104 (84.6) |
5,787/6,684 (86.6) |
0.744 |
86/103 (83.5) |
107/134 (79.9) |
0.776 |
| β-blocker |
61/104 (58.7) |
4,168/6,662 (62.6) |
0.599 |
61/103 (59.2) |
81/133 (60.9) |
0.528 |
| Calcium antagonist |
6/104 (5.8) |
550/6,636 (8.3) |
0.385 |
6/103 (5.8) |
16/132 (12.1) |
0.881 |
| ACEI/ARB |
46/104 (44.2) |
2,886/6,656 (43.4) |
0.474 |
46/103 (44.7) |
52/133 (39.1) |
0.470 |
| Diuretics |
6/104 (5.8) |
412/6,640 (6.2) |
0.644 |
6/103 (5.8) |
11/132 (8.3) |
0.881 |
| Acid inhibitor |
4/103 (3.9) |
157/6,619 (2.4) |
0.175 |
4/102 (3.9) |
3/132 (2.3) |
0.801 |
Data are expressed as n/N(%). “n” means how many patients were taking this drug at 2-year follow up. “N” means how many patients could provide this data. Abbreviations as in Table 1.
After performing PSM, 352 matched pairs were generated from the 2 groups. Possible confounders were almost completely controlled because it was revealed that nearly all the baseline variates showed no significant difference between the 2 groups of propensity matched subjects, as was the case for medication at the 2-year follow up (Tables 1,4). After PSM, the rates of 2-year all-cause death, MACCE and severe bleeding were similar between the 2 groups (20.7% and 17.9%, P=0.317; 23.0% and 19.9%, P=0.288; 0.6% and 1.4%, P=0.453) (Table 2). Kaplan-Meier survival curves revealed consistent results (Figure 3D–F). And multivariable Cox regression analysis after PSM showed that baseline TP was not an independent predictor of all-cause death (HR: 1.21; 95% CI: 0.88–1.67; P=0.240) and MACCE (HR: 1.21; 95% CI: 0.89–1.63; P=0.226), or other ischemic events and severe bleeding (HR: 0.43; 95% CI: 0.08–2.31; P=0.325) (Table 3).
Grading Analysis in Patients With TP
Among patients with TP, the minority (14.0%) were considered as having moderate or severe TP, accounting for 0.3% of the total cohort analyzed. Clinical characteristics including previous MI, WBC count and emergency revascularization showed significantly differences between patients with moderate/severe TP and those with mild TP. Aspirin was administered significantly less frequently in patients with moderate/severe TP than in those with mild TP. Use of other anti-thrombotic drugs including a P2Y12 receptor inhibitor, low molecular weight heparin (LMWH) or fondaparinux, IIb/IIIa receptor antagonists, and other secondary preventions were not significantly different between the 2 groups (Supplementary Table 1). The incidence of all-cause death (33.3% and 19.5%, P=0.033), MACCE (43.1% and 20.4%, P<0.001) and recurrent MI (7.8% and 1.0%, P=0.009) were significantly higher in patients with moderate/severe TP than in those with mild TP. However, severe bleeding and other event risks were similar between the 2 groups. In the univariate Cox regression model, baseline moderate/severe TP was independently associated with all-cause death (HR: 1.90; 95% CI: 1.11–3.26; P=0.019), MACCE (HR: 2.43; 95% CI: 1.50–3.95; P<0.001), recurrent MI (HR: 10.34; 95% CI: 2.32–46.23; P=0.002) and readmission (HR: 2.14; 95% CI: 1.03–4.48; P=0.043) compared with those with mild TP. After multivariate adjustment, baseline moderate/severe TP was independently associated with MACCE (HR: 1.98; 95% CI: 1.11–3.54; P=0.021) and recurrent MI (HR: 8.70; 95% CI: 1.54–49.19; P=0.014) compared with those with mild TP (Supplementary Tables 2,3). Our study may have been underpowered to investigate clinical outcomes in patients with moderate/severe TP because there were only 51 patients with STEMI and moderate/severe TP included. Therefore, because we could not reach any definite conclusions, this information has been included in the Supplementary material. Because STEMI with moderate/severe TP is rare, more data need to be collected and followed up on to study the safety of antithrombotic medication and revascularization in this particular population. Events including ischemic stroke and severe bleeding could not be used as outcome variables because the numbers of these events are too few in one of the two groups studied (Supplementary Tables 1–3).
Discussion
Previous studies have suggested that ACS coexisting with TP not only increases the risk of bleeding, but is also associated with ischemic adverse events, especially the risk of all-cause death. Similar conclusions have been reached in both short-term and long-term studies.1,2,4,13,14
The discussion is that changes in platelet count are accompanied by functional alterations, which may be of greater concern as a probable explanation for an increased risk of thrombus or ischemic events. A direct response to changes in platelet function is changes in platelet volume. Patients who had large volume platelets were reported to have a higher thrombotic potential.15,16
It has previously been reported that mean platelet volume (MPV) could strongly predict 2-year cardiac death in patients with diabetes mellitus and stable coronary artery disease undergoing selective PCI.17
And in patients with STEMI undergoing primary PCI, MPV was also an independent predictor of large intracoronary thrombus burden and short-term mortality.18
However, our serial studies showed that although the risk of in-hospital death and 2-year all-cause death were all worse in patients with STEMI and TP than in those with a normal platelet count, baseline TP was not independently associated with in-hospital and 2-year adverse outcomes.3
These results were not completely consistent with previous studies. One main reason was that the confounders included in the model included baseline hemoglobin. If baseline hemoglobin was not included in the multivariate regression model, baseline TP was found to be the independent predictor of 2-year all-cause death in STEMI patients. Interestingly, we found in most of the references mentioned above the multivariate adjusting models did not including baseline hemoglobin.1–4,13,14
For example, Rubinfeld et al found that patients with AMI and TP were more likely to receive transfusions of red blood cells (OR 3.37, 95% CI 3.25−3.50) and platelets (OR 8.35, 95% CI 7.77−8.97) than AMI patients without TP. It implied that AMI patients with TP had a higher rate of anemia than those without TP. Therefore, baseline hemoglobin might probably be an important confounder, and it was not included in their model.2
TP is a very heterogeneous disease. The platelet number can be reduced, with or without functional changes. Determining the true cause of TP is a difficult and challenging clinical problem. TP results from various causes, but ultimately occurs when platelets are destroyed, sequestered in the body, or not produced. The differential diagnosis of TP is extensive and complex, and there is a significant overlap among disorders.19,20
Weighing the risk of ischemia vs. bleeding is essential. It is generally believed empirically that in patients with >50,000/mm3
platelets who have no history of active bleeding, DAPT is relatively safe, and dosage of heparin should be appropriately reduced during PCI. Clopidogrel should be used as a safer P2Y12 inhibitor. In patients with a platelet count <50,000/mm3
who have no history of active bleeding, there is still insufficient evidence on the safety of DAPT and heparinization. Individuality is emphasized clinically. This study also showed that there was no significant difference in the rate of emergency revascularization (mainly primary PCI) between STEMI patients with TP and those without TP, but the rate of emergency revascularization was significantly reduced in STEMI patients with moderate or severe TP compared to those with mild TP (Supplementary Table 1). This suggests that there is no clear answer as to whether patients with STEMI and moderate or severe TP can tolerate heparinization for primary PCI and long-term DAPT following drug-eluting stenting. Analysis of antiplatelet strategies showed that aspirin and IIb/IIIa receptor antagonist use in STEMI patients with TP was significantly less than that used in those patients without TP. And P2Y12 inhibitors and LMWH/fondaparinux showed no difference between the 2 groups. However, aspirin use was significantly reduced in STEMI patients with moderate or severe TP compared with patients with mild TP, whereas other antithrombotic drugs (P2Y12 inhibitors, LMWH/fondaparinux and IIb/IIIa receptor antagonist) were used similarly between the 2 groups (Supplementary Table 1). Thus, from this real-world situation analysis, we can see clinical caution in the use of aspirin in this particular population and the necessity for P2Y12 inhibitors in STEMI patients regardless of whether they receive PCI.
Hemorrhage is one of the serious complications during DAPT and the perioperative period of PCI. It is significantly correlated with poor clinical prognosis. It is necessary to evaluate the risk of hemorrhage in patients with STEMI and TP, especially the risk of gastrointestinal and intracranial hemorrhage.21,22
The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of American College of Cardiology /American Heart Association Guidelines (CRUSADE) bleeding score recommended by the European guidelines can be applied.23,24
The dosage, type and course of antithrombotic drugs should be reasonably optimized for the patients with middle or high risk of hemorrhage. Meanwhile, equipment strategies, such as the radial artery pathway, and the femoral artery route PCI using vascular closure devices, can reduce the risk of bleeding and improve clinical prognosis.25,26
Another interesting result was that the use of β-blockers and ACEI/ARB in STEMI patients with TP was significantly lower than that used for patients with a normal platelet count. This might be an important factor affecting long-term prognosis. This strange phenomenon has been found in a previous published analysis of nosocomial events in STEMI patients with TP.3
One possible explanation that cannot be excluded is that there is a significant increase of comorbidities of COPD and tumors in the patients with STEMI and TP, compared with those without TP, as revealed in the baseline analysis of this study. Interestingly, after adjusting for these possible confounders at baseline, coexisting with TP was no longer independently associated with all-cause mortality and MACCE. And the results remained consistent after all the baseline differences between the 2 groups were controlled for by PSM, making results more convincing.
With serial observations and analyses in a large enough sample, we have greater confidence in antithrombotic therapy for STEMI patients with TP. Whether the patient receives an emergency PCI, it is feasible according to existing principles and individualized treatment strategies and there is not too much concern about the adverse effects of TP on the prognosis, especially those with mild TP. Coexisting with TP was not associated with increased bleeding or ischemic events under routine antithrombotic therapy according to current guidelines. The main adverse effects might still be the result of comorbidities, such as tumors, rheumatic diseases, hematologic disorders and other systemic diseases. This may be the most important implication of this study. For STEMI patients receiving an emergency PCI, balloon dilation may occur without waiting for blood test results in the emergency room. However, when the results of blood routine examination are returned, and once moderate or severe reduction of platelet count is found, corresponding measures should be taken, such as a corresponding reduction of intraoperative heparin dosage, adjustment of postoperative DAPT strategy, and careful observation of bleeding events. If there is only mild TP, a conventional individualized strategy can be used, considering other high bleeding risk factors.
Several limitations should be taken into consideration. First, ticagrelor was seldom used in China during 2013 and 2014. As the benefit of ticagrelor over clopidogrel in patients with ACS was confirmed in a PLATO trial, clopidogrel was gradually replaced by ticagrelor for the treatment of cases undergoing primary PCI in most centers. The data of this study could only reveal the situation of that year in China.27
Second, data about many secondary preventive drugs were missing during follow up (Table 4
and
Supplementary Table 1). Thus, we cannot analyze accurately the changes in medication usage, which most likely contributes towards the altering of adverse event risks. Finally, as a specialist cardiovascular hospital, we lacked data to determine the cause of TP, as well as co-medications targeting TP (i.e., corticosteroids) or causing TP (i.e., chemotherapy). Moreover, there may be additional confounders that are not controlled for within our model. Nevertheless, this is a large multicenter analysis providing data on cases with STEMI and TP, a relatively rare interdisciplinary disease, in terms of both long-term outcomes and medication situation, and we believe that we have accounted for the most clinically relevant variables in our model.
Conclusions
Patients with STEMI and baseline TP had higher rates of 2-year all-cause death and MACCE. However, baseline TP was not independently associated with 2-year adverse outcomes in patients with STEMI after multivariate adjustment and controlling for baseline differences. Current individualized antithrombotic strategies are relatively safe to use in this population.
Acknowledgments
The authors would like to thank all members from the Scientific Committee, Data Monitoring Committee, and Executive and Steering Committee for their contribution to the CAMI registry. The authors also wish to thank all of the study investigators and coordinators for their great work and all colleagues at the Medical Research & Biometrics Center and Information Technology Center. Many thanks also to Professor Yang Hu and Jingang Yang for their help with statistical analysis and manuscript revision. We appreciate funding support from Professor Jinqing Yuan and Yuejin Yang.
Sources of Funding
This study was funded by: CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009); the Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02); 2014 Special fund for scientific research in the public interest by National Health and Family Planning Commission of the People’s Republic of China (No. 201402001); National Natural Science Foundation of China (No. 81770365); National Key Research and Development Program of China (No. 2016YFC1301301); and Beijing United Heart Foundation (No. BJUHFCSOARF201901-19).
Disclosures
The authors declare no conflicts of interest.
Data Availability
The deidentified participant data will not be shared.
Authorship Declaration
None of the article contents are under consideration for publication in any other journal or have been published in any journal. All authors have participated in the work and have reviewed and agree with the content of the article.
Ethics Statement
This study was registered with ClinicalTrials.gov (NCT01874691) and was approved by the institutional review board of each participating hospital. Ethical approvals were obtained from the Fuwai Hospital Research Ethics Committees, as the main group leader unit of the CAMI registry (Reference number: 431).
Authors’ Contributions
R.L. contributed to all aspects of this study, including study concept and design, data acquisition, statistical analysis and interpretation, drafting and revising the report, and funding. Y.H. contributed to statistical analysis and interpretation. J.Y. contributed to study concept and design, data acquisition and manuscript revision. Q.W., H.Y., Z.W. and S.S. contributed to study concept and design, data acquisition and sub-center ethical issues. J.Y. and Y.Y. contributed to initial study conception and design, and funding.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0781
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