Intern Emerg Med DOI 10.1007/s11739-015-1242-4
IM - ORIGINAL
Dual antiplatelet therapy tailored on platelet function test after coronary stent implantation: a real-world experience Emanuele Cecchi1 • Rossella Marcucci1,2,3 • Marco Chiostri1 • Valerio Mecarocci1 Valentina Spini1 • Lisa Innocenti1 • Raffaella Calabretta1 • Antonella Cordisco1 • Salvatore Mario Romano1 • Rosanna Abbate1,2,3 • Gian Franco Gensini1,2,3,4 • Cristina Giglioli1
•
Received: 21 November 2014 / Accepted: 8 April 2015 Ó SIMI 2015
Abstract Patients’ response to dual antiplatelet therapy (DAPT) is subject to variations and its monitoring allows to individualize this therapy. In this study, we evaluated if a strategy of tailored DAPT after platelet function testing could reduce high on-treatment platelet reactivity (HPR) and improve outcome of patients treated with stent implantation. In 257 patients undergoing percutaneous angioplasty, platelet function was measured by light transmittance aggregometry (LTA) using 10 lM/L adenosine-diphosphate (ADP) and 1 mM arachidonic acid (AA) as agonists. Patients with HPR by ADP (C70 %) were switched to double-dose clopidogrel, ticlopidine, prasugrel or ticagrelor; in patients with HPR by AA (C20 %) acetylsalicylic acid dose was increased if not contraindicated. Platelet function analysis was repeated 48 hours after therapy variation. At 20-month follow-up major adverse cardiovascular events (MACE) and bleedings were assessed. HPR was detected in 97/257 (37.7 %) patients: 69/257 (26.8 %) had HPR by ADP and 71/257 (27.6 %) had HPR by AA. In patients with HPR by ADP or by AA, tailored DAPT determined a significant reduction in residual
& Emanuele Cecchi [email protected] 1
Dipartimento del Cuore e dei Vasi, Azienda OspedalieroUniversitaria Careggi, Viale Morgagni 85, 50134 Florence, Italy
2
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
3
Centre for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases To Develop Novel Therapies, University of Florence, Florence, Italy
4
Centro S. Maria agli Ulivi, Fondazione Don Carlo Gnocchi Onlus IRCCS, Impruneta, Florence, Italy
platelet reactivity. No significant difference in MACE or bleeding occurrence was documented in HPR patients treated with tailored DAPT vs. those without HPR. HPR patients treated with tailored DAPT had significant lower follow-up MACE and deaths vs. 139 HPR patients not switched, even after propensity score analysis. These results suggest that a DAPT tailored on platelet testing can improve antiplatelet response in HPR patients, possibly reducing their thrombotic events to a level similar to nonHPR patients, without increasing the risk of bleeding. Keywords Dual antiplatelet therapy Shifting therapy Percutaneous coronary intervention
Introduction Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and a P2Y12 receptor inhibitor is considered the standard of care for patients with acute coronary syndrome (ACS) or stable angina (SA) undergoing percutaneous coronary intervention (PCI) and stenting [1–5]. Despite the recent availability of newer and more potent antiplatelet drugs, DAPT with ASA and clopidogrel is still the more common therapy in the majority of patients submitted to PCI. Several studies demonstrate that the response to clopidogrel varies among patients, and a diminished responsiveness to this drug, measured as a lower inhibition of platelet activation, has been observed with laboratory tests in a significant proportion of patients treated [6–10]. The variability of individual responsiveness to clopidogrel can lead to significant clinical implications, thus resulting in poor clinical outcomes. Indeed, patients exhibiting high ontreatment platelet reactivity (HPR) by ADP on clopidogrel treatment are at higher risk of recurrent atherothrombotic
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events after PCI, such as stent thrombosis and acute ischemic events [11–18]. Therefore, HPR by ADP could be considered as a failure of clopidogrel treatment, and, possibly, as a modifiable risk factor. In addition, we previously also demonstrated that HPR measured by arachidonic acid (AA) is associated with a worse prognosis [19, 20], as HPR by both ADP and arachidonic acid identifies patients at higher risk of ischemic events [21]. The availability of newer antiplatelet agents, such as prasugrel and ticagrelor, whose efficacy has been recently demonstrated in the setting of acute coronary syndromes [22, 23] allows consideration of a shift to an alternative and more powerful antiplatelet agent as a valuable strategy to overcome HPR by ADP. At our Institution, the opportunity to tailor the antiplatelet therapy is created by the routine performance of platelet function tests in patients submitted to PCI and stenting. The aim of the present study was to assess the feasibility and safety of a ‘‘shifting therapy’’ driven by HPR by ADP or AA and its clinical impact at follow-up in a population of 257 patients on DAPT submitted to PCI and coronary stenting.
Methods From September 2010 to January 2013, 381 consecutive patients with a diagnosis of stable angina (SA) or non-ST elevation ACS were admitted to the cardiac step-down unit of the University of Florence, which is a tertiary center with a high-volume catheterization laboratory. One hundred and twenty-four patients were excluded from the study for the following reasons: coronary anatomy more suitable for coronary artery bypass graft surgery (35 patients), PCI contraindicated for serious comorbidities (21 patients), need for chronic oral anticoagulant therapy (41 patients), coronary anatomy not suitable for any revascularization (10 patients), glycoprotein IIb–IIIa inhibitors’ administration in the acute phase (17 patients) (Fig. 1). Therefore, the study population consisted of 257 patients submitted to PCI and stenting, and treated with a loading dose of ASA 325 mg and clopidogrel 300 mg the day before the PCI in the elective procedures, and with a loading dose of ASA 325 mg and clopidogrel 600 mg in the catheterization laboratory for urgent PCI. After the procedure, all patients were treated with ASA 100 mg/day and clopidogrel 75 mg/day. To prevent contrast-induced nephropathy, elective patients were treated with hyperhydration with saline solution 0.9 % 0.5–1.0 ml/kg/h for 24 h before and after PCI based on left ventricular ejection fraction values and intravenous administration of Nacetylcysteine 600 mg twice/day. Patients affected by
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Fig. 1 Flowchart of patients enrolled in the study
chronic renal failure with a glomerular filtration rate (GFR) \30 ml/min were treated with continuous renal replacement therapy before and after contrast medium administration. Moreover, we selected a group of 139 patients previously treated with PCI and stenting who were non-responders to dual antiplatelet therapy but not shifted to a tailored antiplatelet regimen; from this series of patients, a subgroup of 64 patients was chosen after propensity score analysis for comparison with non-responder patients treated with shifting therapy (see ‘‘Statistical analysis’’ section below). All patients underwent clinical, biohumoral, echocardiographic evaluation before and after PCI. HPR by ADP and AA was tested in all patients within 24 h after PCI by means of light transmittance aggregometry (LTA) method (on 100 mg ASA and 75 mg/day clopidogrel, and after a loading clopidogrel dose of 300–600 mg): HPR by ADP was defined in the presence of LTA by 10 lM/L ADP C 70 % (confirmed twice at a distance of 24 h); HPR by AA was defined in the presence of LTA by 1 mM/L AA C 20 % (confirmed twice at a distance of 24 h). Dual HPR was defined in the presence of HPR by both ADP and AA (LTA by 10 lM/L ADP C 70 % and LTA by 1 mM/L AA C 20 %). Patients with HPR by ADP or AA underwent a second test after 24 h. If HPR by ADP was confirmed, antiplatelet
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therapy was modified in this way: clopidogrel 150 mg/day (13 patients) or ticlopidine 500 mg/day (5 patients) or prasugrel 10 mg/day (36 patients) or ticagrelor 180 mg/day (15 patients). Shifting therapy was preceded by a loading dose of prasugrel or ticagrelor. If HPR by AA was confirmed, aspirin dosage was increased from 100 mg/day to 160 (3 patients) or 325 (29 patients) mg/day if not contraindicated according to clinical judgment. Indeed, in 39 patients with HPR by AA, aspirin dosage was not modified for concurrent ticagrelor therapy or higher risk of gastrointestinal bleeding. All patients underwent a third functional platelet test before hospital discharge 48 h after the shift and were followed up for a mean period of 21.6 ± 9.9 months [median 20 months (13–31)]. Follow-up data included new occurrence of major adverse cardiovascular events (nonfatal myocardial infarction, cardiovascular death, stroke/TIA), repeated target vessel revascularizations (TVR) with PCI and bleedings classified, according to GUSTO criteria [24], as severe or life threatening if they were intracerebral or if they resulted in substantial hemodynamic compromise requiring treatment, moderate bleeding was defined by the need for transfusion and minor bleeding referred to other bleeding, not requiring transfusion or causing hemodynamic compromise. Followup data were obtained by the reports of the scheduled clinical visits performed at 1, 6 and 12 months after hospital discharge or, alternatively, collected by phone interviews by two physicians. Apart from mortality, the cardiovascular and hemorrhagic events reported by patients themselves or by their relatives were then verified, in a blinded manner, by means of hospital records. Informed consent was obtained from each patient and the study protocol has been approved by the appropriate institutional research ethics committee, and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Statistical analysis Statistical analysis has been conducted with IBM-SPSS 20 for Windows software (SPSS Inc, Chicago, IL); in all cases, a p value \0.05 was taken as significant. Continuous variables have been reported as mean ± SD or median (interquartile range IQR); categorical variables have been reported as frequency (percentage). Betweengroup comparisons were made with Student’s t test or Mann–Whitney U test, as needed (continuous data), and Pearson’s chi-square (categorical data). ANOVA test was performed to investigate differences between the mean reduction of ADP 10 lM/L obtained with the different drugs used.
Finally, we used propensity score matching to investigate the effects of therapy shift in a non-responders series with respect to a group of non-responder patients who did not shift. We derived the score from a logistic regression model with the following variables: gender, age, diagnosis, smoking habit, diabetes, hypertension, dyslipidemia, family history of ischemic cardiac disease, body mass index [25 kg/m2, chronic kidney failure and the length of the stents implanted during PCI. In each group, 64 patients were selected for a 1:1 matching, whose baseline characteristics did not significantly differ. Propensity score matching was conducted using a dedicated algorithm in SPSS syntax. Event-free survival was defined as first occurrence during follow-up of MACE (defined as acute coronary syndrome, stroke or TIA, cardiac death, TVR) or bleeding events (according to GUSTO criteria). A Kaplan–Meier model was constructed to investigate event-free survival as well as the occurrence of bleeding complications in those who shifted therapy, and in those who did not.
Results In Table 1, we report the demographic, clinical, angiographic, biohumoral and procedural characteristics of the overall population studied as well as of patients according to HPR by ADP and AA. HPR by ADP or AA was documented in 97 patients of 257 (37.7 %); in 43 patients (16.7 %) dual HPR was observed. Patients with HPR by ADP were more frequently diabetic, they had a higher number of stents implanted, showed a greater total stent length and a higher percentage of stents longer than 30 mm. Patients with HPR by AA were more frequently females, showed greater values of erythrocyte sedimentation rate and a greater total length of stent implanted. No significant differences in clinical and demographic characteristics were found between patients with HPR by both AA and ADP. As angiographic and procedural variables are concerned, patients with HPR by both AA and ADP had a significantly higher number of stents implanted and a higher total stent length. Eighty-three out of 97 (85.6 %) patients with HPR by ADP or AA were suitable for ‘‘shifting therapy’’ because of lack of any contraindications. No significant differences in clinical and laboratory parameters, apart from aggregation test results, as well as follow-up data, were observed in patients with HPR who underwent ‘‘shifting therapy’’ in comparison with patients without HPR (Table 2). No significant differences were observed in the occurrence of cardiovascular events, bleedings, cardiac and non-cardiac death, need for control
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123
71 (62–77)
102 (39.7)
BMI [ 25 kg/m2
84 (32.7)
106 (41.2)
116 (45.1)
72 (28.0)
188 (73.2)
145 (56.4)
84 (32.7)
16 (6.2)
14 (5.4)
55 (50–60)
UA
NSTEMI
Smoking habit
Diabetes
Hypertension
Dyslipidemia
Family history
Chronic renal failure
COPD
LVEF (%)
165/252 (65.5)
Stent length [30 mm
51/68 (75.0)
47 (31–67)
2.67 ± 1.92
24 (34.8)
22 (31.9)
23 (33.3)
21 (18–26)
75 (72–78)
16 (8–24)
203 (174–242)
114/184 (62.0)
36 (23–56)*
2.05 ± 1.33*
62 (33.0)
58 (30.9)
68 (36.1)
15 (13–20)**
52 (41–61)**
1.35 (0.36–7.11)
0.85 (0.71–0.97)
17 (7–30)
205 (168–246)
12.5 (11.0–14.0)
28 (14.9)
55 (50–60)
11 (5.9)
11 (5.9)
61 (32.4)
108 (57.4)
137 (72.9)
45 (23.9)*
87 (46.3)
75 (39.9)
60 (31.9)
53 (28.2)
78 (41.5)
72 (62–77)
132/56 (70.2/29.8)
NO HPR by ADP n = 188 (73.2 %)
* p \ 0.05, ** p \ 0.001 HPR vs. NO HPR (by ADP as well as by AA and both)
Data in table are expressed as frequency (%), median (IR) or mean ± SD when appropriate
2.22 ± 1.53
40 (25–61)
86 (33.5)
3 vessels
Number of stents, mean ± SD
80 (31.1)
2 vessels
Total stents length
91 (35.4)
1 vessel
Number of vessels
Angiographic data
17 (13–21)
LTA by AA (%)
1.60 (0.33–12.46)
1.38 (0.36–8.52)
0.85 (0.72–0.97)
Creatinine (mg/dL)
60 (46–70)
16 (7–28)
TnI (ng/lL)
204 (170–245)
Platelets (*1000/lL)
ESR (mm/h)
LTA by ADP10 (%)
0.86 (0.64–1.00)
13.0 (12.0–14.0)
13.0 (12.0–14.0)
40 (15.6)
Hemoglobin (g/dL)
12 (17.4)
58 (53–60)
3 (4.3)
5 (7.2)
23 (33.3)
37 (53.6)
51 (73.9)
27 (39.1)
29 (42.0)
31 (44.9)
24 (34.8)
14 (20.3)
24 (34.8)
68 (71–77)
49/20 (71.0/29.0)
HPR by ADP n = 69 (26.8 %)
Leukocytosis
Laboratory data
67 (26.1)
CAD-SA
Diagnosis
181/76 (70.4/29.6)
Male/female, n (%)
Age (years)
Clinical features
All patients n = 257
50/70 (71.4)
47 (30–72)
2.56 ± 1.98
29 (40.8)
19 (26.8)
23 (32.4)
26 (22–30)
72 (64–76)
1.90 (0.45–12.41)
0.83 (0.71–0.94)
23 (10–33)
217(186–253)
13.0 (11.0–14.0)
15 (21.4)
59 (52–60)
3 (4.2)
5 (7.0)
25 (35.2)
36 (50.7)
52 (73.2)
21 (29.6)
36 (50.7)
34 (47.9)
21 (29.6)
16 (22.5)
23 (32.4)
74 (62–79)
42/29 (59.2/40.8)
HPR by AA n = 71 (27.6 %)
115/182 (63.2)
38 (23–56)*
2.09 ± 1.30
57 (30.6)
61 (32.8)
68 (36.5)
14 (13–18)**
55 (43–66)**
1.10 (0.33–7.00)
0.86 (0.73–0.97)
16 (6–24)*
199 (168–240)
13.0 (12.0–14.0)
25 (13.4)
55 (50–60)
11 (5.9)
11 (5.9)
59 (31.7)
109 (58.6)
136 (73.1)
51 (27.4)
80 (43.0)
72 (38.7)
63 (33.9)
51 (27.4)
79 (42.5)
71 (62–77)
139/47 (74.7/25.3)*
NO HPR by AA n = 186 (72.4 %)
32 (76.2)
58 (32–78)
2.26 ± 2.25
17 (39.5)
14 (32.6)
12 (27.9)
25 (22–29)
75 (72–79)
2.34 (0.45–12.41)
0.82 (0.73–0.92)
20 (11–27)
210 (186–244)
13 (11–14)
6 (14.3)
58 (52–60)
3 (7.0)
3 (7.0)
16 (37.2)
20 (46.5)
32 (74.4)
15 (34.9)
17 (39.5)
21 (48.8)
14 (32.6)
8 (18.6)
12 (27.9)
72 (62–78)
27/16 (62.8/37.2)
DUAL HPR (by ADP and AA) n = 43 (16.7 %)
Table 1 Clinical, laboratory and angiographic data of the overall population and of patients in relation to responsiveness to clopidogrel and/or ASA
133 (63.3)
38 (24–56)*
1.89 ± 1.30*
69 (32.2)
66 (30.8)
79 (36.9)
15 (13–19)**
56 (44–66)**
1.16 (0.35–7.50)
0.86 (0.71–0.97)
16 (7–28)
202 (168–245)
13 (12–14)
34 (15.9)
55 (50–60)
11 (5.1)
13 (56.1)
68 (31.8)
125 (58.4)
156 (72.9)
57 (26.6)
99 (46.3)
85 (39.7)
70 (32.7)
59 (27.6)
90 (42.1)
71 (62–77)
154/60 (72.0/28.0)
NO DUAL HPR n = 214 (83.3 %)
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Intern Emerg Med Table 2 Clinical, laboratory, angiographic and follow-up data of HPR patients treated with a shifting therapy and of patients without HPR
HPR patients shifted n = 83, 32.3 %
NO HPR patients n = 174, 67.7 %
Male/female, n (%)
56/27 (67.5/32.5)
125/49 (71.8/28.2)
Age (years)
68 (60–78)
72 (62–77)
33 (39.8)
69 (39.7)
CAD-SA
18 (21.7)
49 (28.2)
UA
28 (33.7)
56 (32.2)
NSTEMI
37 (44.6)
69 (39.7)
Smoking habit
39 (47.0)
77 (44.3)
Diabetes
28 (33.7)
44 (25.3)
Hypertension Dyslipidemia
61 (73.5) 46 (55.4)
127 (73.0) 99 (56.9)
Family history
30 (36.1)
54 (31.0)
Clinical features
2
BMI [ 25 kg/m Diagnosis
Chronic renal failure
6 (7.2)
10 (5.7)
COPD
2 (2.4)
12 (6.9)
LVEF (%)
59 (55–60)
55 (50–60)
Leukocytosis
18 (22.0)
22 (12.6)
Hemoglobin (g/dL)
13.0 (12.0–14.0)
13.0 (11.0–14.0)
Platelets (*1000/lL)
206 (179–253)
202 (166–242)
Laboratory data
ESR (mm/h)
18 (9–28)
16 (7–28)
Creatinine (mg/dL)
0.87 (0.74–0.97)
0.85 (0.71–0.97)
TnI (ng/lL)
1.09 (0.36–9.90)
1.47 (0.36–7.78)
LTA by ADP10 (%)
73 (68–78)
51 (38–61)**
LTA by AA (%)
23 (19–27)
15 (13–19)**
Ictus/TIA Stable angina, n (%)
0/71 (0.0) 9 (10.8)
2/159 (1.3) 25 (14.4)
UA/NSTEMI, n (%)
6 (7.2)
14 (8.0)
STEMI, n (%)
1 (1.2)
0 (0.0)
Follow-up data
Hemorrhage, n (%) No hemorrhage
74 (98.7)
168 (98.8)
Major
1 (1.3)
2 (1.2)
Non-cardiac death, n (%)
0/75 (0.0)
0/171 (0.0) 4/171 (2.3)
Cardiac death, n (%)
2/75 (2.7)
MACE, n (%)a
14/75 (18.7)
33/171 (19.3)
Control coronary angiography, n (%)
8/75 (10.7)
29/171 (17.0)
Restenosis
3/72 (4.2)
5/167 (3.0)
De novo non-critical lesions, n (%)
1/74 (1.4)
8/170 (4.7)
De novo critical lesions, n (%)
5/74 (6.8)
13/170 (7.6)
PTCA, n (%)
6/74 (8.1)
17/170 (10.0)
CABG
1/75 (1.3)
0/171 (0.0)
Data in table are expressed as frequency (%), median (IR) or mean ± SD when appropriate a
MACE = UA, NSTEMI, STEMI, ictus/TIA, cardiac death, target vessel revascularization
* p \ 0.05, ** p \ 0.001
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Intern Emerg Med Fig. 2 Values of residual platelet reactivity, measured with light transmittance aggregometry by adenosine diphosphate 10 lM and arachidonic acid, at baseline and after therapy shifting (control)
Fig. 3 Mean values of residual platelet reactivity, measured with light transmittance aggregometry by adenosine diphosphate 10 lM, at baseline and their variations after therapy shifting with different strategies
Fig. 4 Kaplan–Meier curves indicating event-free survival in patients without HPR vs. those with HPR treated with shifting therapy
coronary angiography as well as the occurrence of restenosis or de novo critical and non-critical lesions and need for percutaneous or surgical myocardial revascularization in the subgroup of patients with dual HPR with respect to both groups of HPR patients treated with tailored DAPT and patients without HPR (data not shown).
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Shifting therapy determined a significant decrease in the mean value of residual platelet reactivity in all patients treated with this strategy as expressed by a reduction in 10 microM ADP-LTA values from 73.0 ± 9.2 to 49.3 ± 14.1 % (p \ 0.001) and in 1 mM AA-LTA values from 26.2 ± 15.6 to 18.7 ± 7.7 % (p \ 0.001) (Fig. 2). With regard to the pharmacodynamic data in patients with dual HPR, shifting therapy produced a significant reduction in 10 microM ADP-LTA values from 76.1 ± 6.5 to 50.6 ± 13.6 % (p \ 0.001) and in 1 mM AA-LTA values from 29.6 ± 15.9 to 20.1 ± 5.3 % (p \ 0.001). In all patients with HPR by ADP, residual platelet reactivity was within normal limits after shifting therapy. Thirty-two out of 71 patients with HPR by AA were shifted to an increased aspirin dosage. In Fig. 3, we report the mean values of residual platelet reactivity observed in the different groups of patients who underwent shifting therapy. Patients who shifted from clopidogrel to ticagrelor showed the greatest mean reduction in residual platelet reactivity with the lowest standard deviation. In fact the mean absolute reduction in ADP 10 lmol after the shift was 21.8 ± 11.0 % for clopidogrel 150 mg/die, 24.8 ± 13.1 % for prasugrel, 37.9 ± 7.5 % for ticagrelor, 17.4 ± 12.2 % for ticlopidine, with an overall p \ 0.001 at ANOVA vs. all others. At a median 20-month follow-up, no significant difference was observed in the incidence of MACE in our study population between patient responders and those with HPR submitted to shifting therapy (Fig. 4). Accordingly, no significant difference in the incidence of bleeding events was documented (Fig. 5). Finally, we compared the two groups of patients with HPR, one treated with tailored DAPT regimen and the other who was not submitted to a shifted therapy. In Table 3, we report the clinical, angiographic and follow-up data of HPR patients in relation to the use of a shifting therapy after propensity score analysis. HPR patients not submitted to shifting therapy exhibited a significantly higher rate of MACE and all-cause death at follow-up with respect to those treated with a tailored antiplatelet regimen.
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Discussion A large number of studies document that high on-treatment platelet reactivity (HPR) by ADP is a prognostic marker for ischemic events, in particular stent thrombosis and cardiovascular death [11–18]. In addition, some data suggest that a global high platelet reactivity—by both ADP and AA—is associated with a worse prognosis in patients with acute coronary syndromes undergoing PCI [21].
Fig. 5 Kaplan–Meier curves indicating major bleeding-free survival in patients without HPR vs. those with HPR treated with shifting therapy
Table 3 Clinical, angiographic and follow-up data of HPR patients in relation to the use of a shifting therapy after propensity score analysis
The results of these studies have led to the novel concept of ‘‘tailored antiplatelet therapy’’, a strategy that provides the switch to a higher dose of antiplatelets or to newer antiplatelet drugs, such as prasugrel or ticagrelor, after the assessment of platelet function test. On the other hand, we do not have yet strong evidences that overcoming high platelet reactivity can improve prognosis in these patients. Indeed, both GRAVITAS [25] and ARCTIC [26] trials fail to demonstrate a clinical benefit of an antiplatelet therapy tailored on platelet function tests. However, both trials have a number of limitations, and do not correctly respond to the question whether laboratory monitoring may help clinicians to choose the correct antiplatelet therapy. Moreover, both trials do not demonstrate efficient correction of high platelet reactivity. In GRAVITAS [25], a strategy based on the double dosage of clopidogrel was used (150 mg/die), and in about 40 % of patients, high platelet reactivity persisted after the introduction of increased dosage. In this study, platelet treatment was modified (clopidogrel from 75 to 150 mg/day) without proving the efficacy of this intervention in terms of platelet function inhibition immediately after the procedure but only at 30 days and at 6-month follow-up, even without a significant reduction in terms of cardiovascular events. After GRAVITAS trial conclusion, newer, more potent, antiplatelet drugs became progressively available, and in our
HPR patients shifted n = 64
HPR patients not shifted n = 64
p value
Clinical features Male/female, n (%)
38/26 (59.4/40.6)
43/21 (67.2/32.8)
0.359
Age (years) BMI [ 25 kg/m2
70.2 ± 10.5 29 (45.3)
69.3 ± 10.2 27 (42.2)
0.633 0.722
UA
28 (43.8)
30 (46.9)
0.723
NSTEMI–STEMI
36 (56.2)
34 (53.1)
Smoking habit
28 (43.8)
30 (46.9)
Diabetes
20 (31.2)
19 (29.7)
0.848
Hypertension
47 (73.4)
45 (70.3)
0.694
Dyslipidemia
37 (57.8)
38 (59.4)
0.858
Family history
22 (34.4)
17 (26.6)
0.337
Chronic renal failure
6 (9.4)
3 (4.7)
0.300
Total stent length
53.0 ± 30.2
54.2 ± 40.5
0.851
Stent length [30 mm
48 (75.0)
39 (60.9)
0.088
All-cause death, n (%)
0/56 (0.0)
9/64 (14.1)
0.004
MACE, n (%)a
7/56 (12.5)
23/64 (35.9)
0.003
Diagnosis
0.723
Follow-up data
Data in table are expressed as frequency (%), median (IR) or mean ± SD when appropriate a
MACE = UA, NSTEMI, STEMI, ictus/TIA, cardiac death, target vessel revascularization
* p \ 0.05, ** p \ 0.001
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study, several HPR patients were switched to these novel antiplatelets. So, at variance with GRAVITAS in which HPR patients were randomized to clopidogrel 75 mg/die vs. 150 mg/die, we had multiple patterns of tailored DAPT (ticlopidine, clopidogrel 150 mg/die, prasugrel or ticagrelor). Moreover, in 32 patients, we also increased the mean daily dosage of acetylsalicylic acid, when HPR by AA was detected, and if not contraindicated, an approach not adopted in GRAVITAS trial in which aspirin treatment was used at a dose of 75–162 mg daily. Finally, at variance with GRAVITAS, we used LTA by ADP instead of verifyNow P2Y12 test for tailoring DAPT. In line with this, are the results of RECLOSE-2 ACS registry that find a more than twofold higher risk for allcause death, myocardial infarction, stent thrombosis or stroke in HPR patients despite up-titrating the dose of clopidogrel [27]. In ARCTIC [26], only 11 % of patients were treated with an alternative antiplatelet drug such as prasugrel, and again the majority of patients were treated with an increased dosage of clopidogrel or with an additional use of glycoprotein IIb/IIIa inhibitors. Finally, it was calculated that the number of patients enrolled in ARCTIC was insufficient to adequately answer the question if a strategy based on laboratory monitoring is better than a standard strategy [26]. On the other hand, a recent metanalysis by Aradi et al. [27] demonstrates that intensifying antiplatelet therapy on the basis of a platelet reactivity test reduces cardiovascular mortality and stent thrombosis after PCI with the net benefit of this approach. In this study, the authors report the use only of double-dose clopidogrel or prasugrel. More recently, in another study on ACS patients, they demonstrate that switching HPR patients to prasugrel reduces thrombotic and bleeding events to a level similar to those without HPR, while switching to double-dose clopidogrel results in higher risk for both thrombotic and bleeding events [28]. Also our data reporting the experience with ticagrelor are in line with these results. In our study, we confirm that about 27 % of patients undergoing PCI show HPR on DAPT, and we have treated them by modifying the antiplatelet treatment to effectively reduce the high platelet reactivity. Indeed, in all patients, we demonstrate the absence of HPR after antiplatelet therapy variation. We find that the risk of patients with initial HPR becomes similar to that of patients with an adequate platelet inhibition. Indeed in our patients, we do not find differences in terms of thrombotic complications at follow-up between patients without HPR and those who reached adequate platelet reactivity after shifting. Moreover, when compared with a propensity score-matched cohort of HPR patients not treated with a shifting therapy,
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HPR patients treated with a tailored dual antiplatelet regimen exhibit a significantly lower rate of MACE and deaths at follow-up. These results suggest the efficacy of the tailored antiplatelet treatment. In our study, we observe a significant reduction in the degree of platelet inhibition, especially with the use of newer antiplatelet drugs. In particular, the use of ticagrelor determines a significantly greater reduction in residual platelet reactivity with a more predictable effect. This result might be explained by the fact that the resistance to clopidogrel driven by genetic mutations cannot be completely overcome by doubling the clopidogrel dose or switching to prasugrel, which differently from ticagrelor, is a prodrug and shares cytochromes with clopidogrel for its metabolic activation. However, whether the improvement in outcome of our patients was determined by a reduction in HPR or by the use of newer antiplatelet drugs itself, associated per se with a reduction of cardiovascular events, is difficult to establish. Our study demonstrates that HPR patients can benefit from a tailored antiplatelet approach. Interestingly, in our study, as previously demonstrated, HPR is associated with greater total stent length and diabetes suggesting that patients with more severe coronary artery disease may further benefit from a strategy based on a tailored antiplatelet therapy. A limitation of our study is the low number of patients enrolled for which this study is underpowered to reliably detect differences in the occurrence of major adverse cardiovascular events, especially considering the size of the GRAVITAS and ARCTIC trials. In particular, the propensity-matched analysis critically reduced the total number of patients enrolled so these results should be interpreted cautiously. Another study limitation is that this is not a randomized trial. Moreover, in our study, patients with stable CAD were enrolled, for whom data on newer antiplatelet drugs efficacy are not available. In conclusion, these results mirror a real-world experience in which we tailored our antiplatelet treatment on platelet function test in high-risk cardiovascular patients. The lack of an increased risk of bleeding at follow-up suggests that this approach is safe. Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.
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IM - ORIGINAL
Dual antiplatelet therapy tailored on platelet function test after coronary stent implantation: a real-world experience Emanuele Cecchi1 • Rossella Marcucci1,2,3 • Marco Chiostri1 • Valerio Mecarocci1 Valentina Spini1 • Lisa Innocenti1 • Raffaella Calabretta1 • Antonella Cordisco1 • Salvatore Mario Romano1 • Rosanna Abbate1,2,3 • Gian Franco Gensini1,2,3,4 • Cristina Giglioli1
•
Received: 21 November 2014 / Accepted: 8 April 2015 Ó SIMI 2015
Abstract Patients’ response to dual antiplatelet therapy (DAPT) is subject to variations and its monitoring allows to individualize this therapy. In this study, we evaluated if a strategy of tailored DAPT after platelet function testing could reduce high on-treatment platelet reactivity (HPR) and improve outcome of patients treated with stent implantation. In 257 patients undergoing percutaneous angioplasty, platelet function was measured by light transmittance aggregometry (LTA) using 10 lM/L adenosine-diphosphate (ADP) and 1 mM arachidonic acid (AA) as agonists. Patients with HPR by ADP (C70 %) were switched to double-dose clopidogrel, ticlopidine, prasugrel or ticagrelor; in patients with HPR by AA (C20 %) acetylsalicylic acid dose was increased if not contraindicated. Platelet function analysis was repeated 48 hours after therapy variation. At 20-month follow-up major adverse cardiovascular events (MACE) and bleedings were assessed. HPR was detected in 97/257 (37.7 %) patients: 69/257 (26.8 %) had HPR by ADP and 71/257 (27.6 %) had HPR by AA. In patients with HPR by ADP or by AA, tailored DAPT determined a significant reduction in residual
& Emanuele Cecchi [email protected] 1
Dipartimento del Cuore e dei Vasi, Azienda OspedalieroUniversitaria Careggi, Viale Morgagni 85, 50134 Florence, Italy
2
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
3
Centre for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases To Develop Novel Therapies, University of Florence, Florence, Italy
4
Centro S. Maria agli Ulivi, Fondazione Don Carlo Gnocchi Onlus IRCCS, Impruneta, Florence, Italy
platelet reactivity. No significant difference in MACE or bleeding occurrence was documented in HPR patients treated with tailored DAPT vs. those without HPR. HPR patients treated with tailored DAPT had significant lower follow-up MACE and deaths vs. 139 HPR patients not switched, even after propensity score analysis. These results suggest that a DAPT tailored on platelet testing can improve antiplatelet response in HPR patients, possibly reducing their thrombotic events to a level similar to nonHPR patients, without increasing the risk of bleeding. Keywords Dual antiplatelet therapy Shifting therapy Percutaneous coronary intervention
Introduction Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and a P2Y12 receptor inhibitor is considered the standard of care for patients with acute coronary syndrome (ACS) or stable angina (SA) undergoing percutaneous coronary intervention (PCI) and stenting [1–5]. Despite the recent availability of newer and more potent antiplatelet drugs, DAPT with ASA and clopidogrel is still the more common therapy in the majority of patients submitted to PCI. Several studies demonstrate that the response to clopidogrel varies among patients, and a diminished responsiveness to this drug, measured as a lower inhibition of platelet activation, has been observed with laboratory tests in a significant proportion of patients treated [6–10]. The variability of individual responsiveness to clopidogrel can lead to significant clinical implications, thus resulting in poor clinical outcomes. Indeed, patients exhibiting high ontreatment platelet reactivity (HPR) by ADP on clopidogrel treatment are at higher risk of recurrent atherothrombotic
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events after PCI, such as stent thrombosis and acute ischemic events [11–18]. Therefore, HPR by ADP could be considered as a failure of clopidogrel treatment, and, possibly, as a modifiable risk factor. In addition, we previously also demonstrated that HPR measured by arachidonic acid (AA) is associated with a worse prognosis [19, 20], as HPR by both ADP and arachidonic acid identifies patients at higher risk of ischemic events [21]. The availability of newer antiplatelet agents, such as prasugrel and ticagrelor, whose efficacy has been recently demonstrated in the setting of acute coronary syndromes [22, 23] allows consideration of a shift to an alternative and more powerful antiplatelet agent as a valuable strategy to overcome HPR by ADP. At our Institution, the opportunity to tailor the antiplatelet therapy is created by the routine performance of platelet function tests in patients submitted to PCI and stenting. The aim of the present study was to assess the feasibility and safety of a ‘‘shifting therapy’’ driven by HPR by ADP or AA and its clinical impact at follow-up in a population of 257 patients on DAPT submitted to PCI and coronary stenting.
Methods From September 2010 to January 2013, 381 consecutive patients with a diagnosis of stable angina (SA) or non-ST elevation ACS were admitted to the cardiac step-down unit of the University of Florence, which is a tertiary center with a high-volume catheterization laboratory. One hundred and twenty-four patients were excluded from the study for the following reasons: coronary anatomy more suitable for coronary artery bypass graft surgery (35 patients), PCI contraindicated for serious comorbidities (21 patients), need for chronic oral anticoagulant therapy (41 patients), coronary anatomy not suitable for any revascularization (10 patients), glycoprotein IIb–IIIa inhibitors’ administration in the acute phase (17 patients) (Fig. 1). Therefore, the study population consisted of 257 patients submitted to PCI and stenting, and treated with a loading dose of ASA 325 mg and clopidogrel 300 mg the day before the PCI in the elective procedures, and with a loading dose of ASA 325 mg and clopidogrel 600 mg in the catheterization laboratory for urgent PCI. After the procedure, all patients were treated with ASA 100 mg/day and clopidogrel 75 mg/day. To prevent contrast-induced nephropathy, elective patients were treated with hyperhydration with saline solution 0.9 % 0.5–1.0 ml/kg/h for 24 h before and after PCI based on left ventricular ejection fraction values and intravenous administration of Nacetylcysteine 600 mg twice/day. Patients affected by
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Fig. 1 Flowchart of patients enrolled in the study
chronic renal failure with a glomerular filtration rate (GFR) \30 ml/min were treated with continuous renal replacement therapy before and after contrast medium administration. Moreover, we selected a group of 139 patients previously treated with PCI and stenting who were non-responders to dual antiplatelet therapy but not shifted to a tailored antiplatelet regimen; from this series of patients, a subgroup of 64 patients was chosen after propensity score analysis for comparison with non-responder patients treated with shifting therapy (see ‘‘Statistical analysis’’ section below). All patients underwent clinical, biohumoral, echocardiographic evaluation before and after PCI. HPR by ADP and AA was tested in all patients within 24 h after PCI by means of light transmittance aggregometry (LTA) method (on 100 mg ASA and 75 mg/day clopidogrel, and after a loading clopidogrel dose of 300–600 mg): HPR by ADP was defined in the presence of LTA by 10 lM/L ADP C 70 % (confirmed twice at a distance of 24 h); HPR by AA was defined in the presence of LTA by 1 mM/L AA C 20 % (confirmed twice at a distance of 24 h). Dual HPR was defined in the presence of HPR by both ADP and AA (LTA by 10 lM/L ADP C 70 % and LTA by 1 mM/L AA C 20 %). Patients with HPR by ADP or AA underwent a second test after 24 h. If HPR by ADP was confirmed, antiplatelet
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therapy was modified in this way: clopidogrel 150 mg/day (13 patients) or ticlopidine 500 mg/day (5 patients) or prasugrel 10 mg/day (36 patients) or ticagrelor 180 mg/day (15 patients). Shifting therapy was preceded by a loading dose of prasugrel or ticagrelor. If HPR by AA was confirmed, aspirin dosage was increased from 100 mg/day to 160 (3 patients) or 325 (29 patients) mg/day if not contraindicated according to clinical judgment. Indeed, in 39 patients with HPR by AA, aspirin dosage was not modified for concurrent ticagrelor therapy or higher risk of gastrointestinal bleeding. All patients underwent a third functional platelet test before hospital discharge 48 h after the shift and were followed up for a mean period of 21.6 ± 9.9 months [median 20 months (13–31)]. Follow-up data included new occurrence of major adverse cardiovascular events (nonfatal myocardial infarction, cardiovascular death, stroke/TIA), repeated target vessel revascularizations (TVR) with PCI and bleedings classified, according to GUSTO criteria [24], as severe or life threatening if they were intracerebral or if they resulted in substantial hemodynamic compromise requiring treatment, moderate bleeding was defined by the need for transfusion and minor bleeding referred to other bleeding, not requiring transfusion or causing hemodynamic compromise. Followup data were obtained by the reports of the scheduled clinical visits performed at 1, 6 and 12 months after hospital discharge or, alternatively, collected by phone interviews by two physicians. Apart from mortality, the cardiovascular and hemorrhagic events reported by patients themselves or by their relatives were then verified, in a blinded manner, by means of hospital records. Informed consent was obtained from each patient and the study protocol has been approved by the appropriate institutional research ethics committee, and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Statistical analysis Statistical analysis has been conducted with IBM-SPSS 20 for Windows software (SPSS Inc, Chicago, IL); in all cases, a p value \0.05 was taken as significant. Continuous variables have been reported as mean ± SD or median (interquartile range IQR); categorical variables have been reported as frequency (percentage). Betweengroup comparisons were made with Student’s t test or Mann–Whitney U test, as needed (continuous data), and Pearson’s chi-square (categorical data). ANOVA test was performed to investigate differences between the mean reduction of ADP 10 lM/L obtained with the different drugs used.
Finally, we used propensity score matching to investigate the effects of therapy shift in a non-responders series with respect to a group of non-responder patients who did not shift. We derived the score from a logistic regression model with the following variables: gender, age, diagnosis, smoking habit, diabetes, hypertension, dyslipidemia, family history of ischemic cardiac disease, body mass index [25 kg/m2, chronic kidney failure and the length of the stents implanted during PCI. In each group, 64 patients were selected for a 1:1 matching, whose baseline characteristics did not significantly differ. Propensity score matching was conducted using a dedicated algorithm in SPSS syntax. Event-free survival was defined as first occurrence during follow-up of MACE (defined as acute coronary syndrome, stroke or TIA, cardiac death, TVR) or bleeding events (according to GUSTO criteria). A Kaplan–Meier model was constructed to investigate event-free survival as well as the occurrence of bleeding complications in those who shifted therapy, and in those who did not.
Results In Table 1, we report the demographic, clinical, angiographic, biohumoral and procedural characteristics of the overall population studied as well as of patients according to HPR by ADP and AA. HPR by ADP or AA was documented in 97 patients of 257 (37.7 %); in 43 patients (16.7 %) dual HPR was observed. Patients with HPR by ADP were more frequently diabetic, they had a higher number of stents implanted, showed a greater total stent length and a higher percentage of stents longer than 30 mm. Patients with HPR by AA were more frequently females, showed greater values of erythrocyte sedimentation rate and a greater total length of stent implanted. No significant differences in clinical and demographic characteristics were found between patients with HPR by both AA and ADP. As angiographic and procedural variables are concerned, patients with HPR by both AA and ADP had a significantly higher number of stents implanted and a higher total stent length. Eighty-three out of 97 (85.6 %) patients with HPR by ADP or AA were suitable for ‘‘shifting therapy’’ because of lack of any contraindications. No significant differences in clinical and laboratory parameters, apart from aggregation test results, as well as follow-up data, were observed in patients with HPR who underwent ‘‘shifting therapy’’ in comparison with patients without HPR (Table 2). No significant differences were observed in the occurrence of cardiovascular events, bleedings, cardiac and non-cardiac death, need for control
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123
71 (62–77)
102 (39.7)
BMI [ 25 kg/m2
84 (32.7)
106 (41.2)
116 (45.1)
72 (28.0)
188 (73.2)
145 (56.4)
84 (32.7)
16 (6.2)
14 (5.4)
55 (50–60)
UA
NSTEMI
Smoking habit
Diabetes
Hypertension
Dyslipidemia
Family history
Chronic renal failure
COPD
LVEF (%)
165/252 (65.5)
Stent length [30 mm
51/68 (75.0)
47 (31–67)
2.67 ± 1.92
24 (34.8)
22 (31.9)
23 (33.3)
21 (18–26)
75 (72–78)
16 (8–24)
203 (174–242)
114/184 (62.0)
36 (23–56)*
2.05 ± 1.33*
62 (33.0)
58 (30.9)
68 (36.1)
15 (13–20)**
52 (41–61)**
1.35 (0.36–7.11)
0.85 (0.71–0.97)
17 (7–30)
205 (168–246)
12.5 (11.0–14.0)
28 (14.9)
55 (50–60)
11 (5.9)
11 (5.9)
61 (32.4)
108 (57.4)
137 (72.9)
45 (23.9)*
87 (46.3)
75 (39.9)
60 (31.9)
53 (28.2)
78 (41.5)
72 (62–77)
132/56 (70.2/29.8)
NO HPR by ADP n = 188 (73.2 %)
* p \ 0.05, ** p \ 0.001 HPR vs. NO HPR (by ADP as well as by AA and both)
Data in table are expressed as frequency (%), median (IR) or mean ± SD when appropriate
2.22 ± 1.53
40 (25–61)
86 (33.5)
3 vessels
Number of stents, mean ± SD
80 (31.1)
2 vessels
Total stents length
91 (35.4)
1 vessel
Number of vessels
Angiographic data
17 (13–21)
LTA by AA (%)
1.60 (0.33–12.46)
1.38 (0.36–8.52)
0.85 (0.72–0.97)
Creatinine (mg/dL)
60 (46–70)
16 (7–28)
TnI (ng/lL)
204 (170–245)
Platelets (*1000/lL)
ESR (mm/h)
LTA by ADP10 (%)
0.86 (0.64–1.00)
13.0 (12.0–14.0)
13.0 (12.0–14.0)
40 (15.6)
Hemoglobin (g/dL)
12 (17.4)
58 (53–60)
3 (4.3)
5 (7.2)
23 (33.3)
37 (53.6)
51 (73.9)
27 (39.1)
29 (42.0)
31 (44.9)
24 (34.8)
14 (20.3)
24 (34.8)
68 (71–77)
49/20 (71.0/29.0)
HPR by ADP n = 69 (26.8 %)
Leukocytosis
Laboratory data
67 (26.1)
CAD-SA
Diagnosis
181/76 (70.4/29.6)
Male/female, n (%)
Age (years)
Clinical features
All patients n = 257
50/70 (71.4)
47 (30–72)
2.56 ± 1.98
29 (40.8)
19 (26.8)
23 (32.4)
26 (22–30)
72 (64–76)
1.90 (0.45–12.41)
0.83 (0.71–0.94)
23 (10–33)
217(186–253)
13.0 (11.0–14.0)
15 (21.4)
59 (52–60)
3 (4.2)
5 (7.0)
25 (35.2)
36 (50.7)
52 (73.2)
21 (29.6)
36 (50.7)
34 (47.9)
21 (29.6)
16 (22.5)
23 (32.4)
74 (62–79)
42/29 (59.2/40.8)
HPR by AA n = 71 (27.6 %)
115/182 (63.2)
38 (23–56)*
2.09 ± 1.30
57 (30.6)
61 (32.8)
68 (36.5)
14 (13–18)**
55 (43–66)**
1.10 (0.33–7.00)
0.86 (0.73–0.97)
16 (6–24)*
199 (168–240)
13.0 (12.0–14.0)
25 (13.4)
55 (50–60)
11 (5.9)
11 (5.9)
59 (31.7)
109 (58.6)
136 (73.1)
51 (27.4)
80 (43.0)
72 (38.7)
63 (33.9)
51 (27.4)
79 (42.5)
71 (62–77)
139/47 (74.7/25.3)*
NO HPR by AA n = 186 (72.4 %)
32 (76.2)
58 (32–78)
2.26 ± 2.25
17 (39.5)
14 (32.6)
12 (27.9)
25 (22–29)
75 (72–79)
2.34 (0.45–12.41)
0.82 (0.73–0.92)
20 (11–27)
210 (186–244)
13 (11–14)
6 (14.3)
58 (52–60)
3 (7.0)
3 (7.0)
16 (37.2)
20 (46.5)
32 (74.4)
15 (34.9)
17 (39.5)
21 (48.8)
14 (32.6)
8 (18.6)
12 (27.9)
72 (62–78)
27/16 (62.8/37.2)
DUAL HPR (by ADP and AA) n = 43 (16.7 %)
Table 1 Clinical, laboratory and angiographic data of the overall population and of patients in relation to responsiveness to clopidogrel and/or ASA
133 (63.3)
38 (24–56)*
1.89 ± 1.30*
69 (32.2)
66 (30.8)
79 (36.9)
15 (13–19)**
56 (44–66)**
1.16 (0.35–7.50)
0.86 (0.71–0.97)
16 (7–28)
202 (168–245)
13 (12–14)
34 (15.9)
55 (50–60)
11 (5.1)
13 (56.1)
68 (31.8)
125 (58.4)
156 (72.9)
57 (26.6)
99 (46.3)
85 (39.7)
70 (32.7)
59 (27.6)
90 (42.1)
71 (62–77)
154/60 (72.0/28.0)
NO DUAL HPR n = 214 (83.3 %)
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Intern Emerg Med Table 2 Clinical, laboratory, angiographic and follow-up data of HPR patients treated with a shifting therapy and of patients without HPR
HPR patients shifted n = 83, 32.3 %
NO HPR patients n = 174, 67.7 %
Male/female, n (%)
56/27 (67.5/32.5)
125/49 (71.8/28.2)
Age (years)
68 (60–78)
72 (62–77)
33 (39.8)
69 (39.7)
CAD-SA
18 (21.7)
49 (28.2)
UA
28 (33.7)
56 (32.2)
NSTEMI
37 (44.6)
69 (39.7)
Smoking habit
39 (47.0)
77 (44.3)
Diabetes
28 (33.7)
44 (25.3)
Hypertension Dyslipidemia
61 (73.5) 46 (55.4)
127 (73.0) 99 (56.9)
Family history
30 (36.1)
54 (31.0)
Clinical features
2
BMI [ 25 kg/m Diagnosis
Chronic renal failure
6 (7.2)
10 (5.7)
COPD
2 (2.4)
12 (6.9)
LVEF (%)
59 (55–60)
55 (50–60)
Leukocytosis
18 (22.0)
22 (12.6)
Hemoglobin (g/dL)
13.0 (12.0–14.0)
13.0 (11.0–14.0)
Platelets (*1000/lL)
206 (179–253)
202 (166–242)
Laboratory data
ESR (mm/h)
18 (9–28)
16 (7–28)
Creatinine (mg/dL)
0.87 (0.74–0.97)
0.85 (0.71–0.97)
TnI (ng/lL)
1.09 (0.36–9.90)
1.47 (0.36–7.78)
LTA by ADP10 (%)
73 (68–78)
51 (38–61)**
LTA by AA (%)
23 (19–27)
15 (13–19)**
Ictus/TIA Stable angina, n (%)
0/71 (0.0) 9 (10.8)
2/159 (1.3) 25 (14.4)
UA/NSTEMI, n (%)
6 (7.2)
14 (8.0)
STEMI, n (%)
1 (1.2)
0 (0.0)
Follow-up data
Hemorrhage, n (%) No hemorrhage
74 (98.7)
168 (98.8)
Major
1 (1.3)
2 (1.2)
Non-cardiac death, n (%)
0/75 (0.0)
0/171 (0.0) 4/171 (2.3)
Cardiac death, n (%)
2/75 (2.7)
MACE, n (%)a
14/75 (18.7)
33/171 (19.3)
Control coronary angiography, n (%)
8/75 (10.7)
29/171 (17.0)
Restenosis
3/72 (4.2)
5/167 (3.0)
De novo non-critical lesions, n (%)
1/74 (1.4)
8/170 (4.7)
De novo critical lesions, n (%)
5/74 (6.8)
13/170 (7.6)
PTCA, n (%)
6/74 (8.1)
17/170 (10.0)
CABG
1/75 (1.3)
0/171 (0.0)
Data in table are expressed as frequency (%), median (IR) or mean ± SD when appropriate a
MACE = UA, NSTEMI, STEMI, ictus/TIA, cardiac death, target vessel revascularization
* p \ 0.05, ** p \ 0.001
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Intern Emerg Med Fig. 2 Values of residual platelet reactivity, measured with light transmittance aggregometry by adenosine diphosphate 10 lM and arachidonic acid, at baseline and after therapy shifting (control)
Fig. 3 Mean values of residual platelet reactivity, measured with light transmittance aggregometry by adenosine diphosphate 10 lM, at baseline and their variations after therapy shifting with different strategies
Fig. 4 Kaplan–Meier curves indicating event-free survival in patients without HPR vs. those with HPR treated with shifting therapy
coronary angiography as well as the occurrence of restenosis or de novo critical and non-critical lesions and need for percutaneous or surgical myocardial revascularization in the subgroup of patients with dual HPR with respect to both groups of HPR patients treated with tailored DAPT and patients without HPR (data not shown).
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Shifting therapy determined a significant decrease in the mean value of residual platelet reactivity in all patients treated with this strategy as expressed by a reduction in 10 microM ADP-LTA values from 73.0 ± 9.2 to 49.3 ± 14.1 % (p \ 0.001) and in 1 mM AA-LTA values from 26.2 ± 15.6 to 18.7 ± 7.7 % (p \ 0.001) (Fig. 2). With regard to the pharmacodynamic data in patients with dual HPR, shifting therapy produced a significant reduction in 10 microM ADP-LTA values from 76.1 ± 6.5 to 50.6 ± 13.6 % (p \ 0.001) and in 1 mM AA-LTA values from 29.6 ± 15.9 to 20.1 ± 5.3 % (p \ 0.001). In all patients with HPR by ADP, residual platelet reactivity was within normal limits after shifting therapy. Thirty-two out of 71 patients with HPR by AA were shifted to an increased aspirin dosage. In Fig. 3, we report the mean values of residual platelet reactivity observed in the different groups of patients who underwent shifting therapy. Patients who shifted from clopidogrel to ticagrelor showed the greatest mean reduction in residual platelet reactivity with the lowest standard deviation. In fact the mean absolute reduction in ADP 10 lmol after the shift was 21.8 ± 11.0 % for clopidogrel 150 mg/die, 24.8 ± 13.1 % for prasugrel, 37.9 ± 7.5 % for ticagrelor, 17.4 ± 12.2 % for ticlopidine, with an overall p \ 0.001 at ANOVA vs. all others. At a median 20-month follow-up, no significant difference was observed in the incidence of MACE in our study population between patient responders and those with HPR submitted to shifting therapy (Fig. 4). Accordingly, no significant difference in the incidence of bleeding events was documented (Fig. 5). Finally, we compared the two groups of patients with HPR, one treated with tailored DAPT regimen and the other who was not submitted to a shifted therapy. In Table 3, we report the clinical, angiographic and follow-up data of HPR patients in relation to the use of a shifting therapy after propensity score analysis. HPR patients not submitted to shifting therapy exhibited a significantly higher rate of MACE and all-cause death at follow-up with respect to those treated with a tailored antiplatelet regimen.
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Discussion A large number of studies document that high on-treatment platelet reactivity (HPR) by ADP is a prognostic marker for ischemic events, in particular stent thrombosis and cardiovascular death [11–18]. In addition, some data suggest that a global high platelet reactivity—by both ADP and AA—is associated with a worse prognosis in patients with acute coronary syndromes undergoing PCI [21].
Fig. 5 Kaplan–Meier curves indicating major bleeding-free survival in patients without HPR vs. those with HPR treated with shifting therapy
Table 3 Clinical, angiographic and follow-up data of HPR patients in relation to the use of a shifting therapy after propensity score analysis
The results of these studies have led to the novel concept of ‘‘tailored antiplatelet therapy’’, a strategy that provides the switch to a higher dose of antiplatelets or to newer antiplatelet drugs, such as prasugrel or ticagrelor, after the assessment of platelet function test. On the other hand, we do not have yet strong evidences that overcoming high platelet reactivity can improve prognosis in these patients. Indeed, both GRAVITAS [25] and ARCTIC [26] trials fail to demonstrate a clinical benefit of an antiplatelet therapy tailored on platelet function tests. However, both trials have a number of limitations, and do not correctly respond to the question whether laboratory monitoring may help clinicians to choose the correct antiplatelet therapy. Moreover, both trials do not demonstrate efficient correction of high platelet reactivity. In GRAVITAS [25], a strategy based on the double dosage of clopidogrel was used (150 mg/die), and in about 40 % of patients, high platelet reactivity persisted after the introduction of increased dosage. In this study, platelet treatment was modified (clopidogrel from 75 to 150 mg/day) without proving the efficacy of this intervention in terms of platelet function inhibition immediately after the procedure but only at 30 days and at 6-month follow-up, even without a significant reduction in terms of cardiovascular events. After GRAVITAS trial conclusion, newer, more potent, antiplatelet drugs became progressively available, and in our
HPR patients shifted n = 64
HPR patients not shifted n = 64
p value
Clinical features Male/female, n (%)
38/26 (59.4/40.6)
43/21 (67.2/32.8)
0.359
Age (years) BMI [ 25 kg/m2
70.2 ± 10.5 29 (45.3)
69.3 ± 10.2 27 (42.2)
0.633 0.722
UA
28 (43.8)
30 (46.9)
0.723
NSTEMI–STEMI
36 (56.2)
34 (53.1)
Smoking habit
28 (43.8)
30 (46.9)
Diabetes
20 (31.2)
19 (29.7)
0.848
Hypertension
47 (73.4)
45 (70.3)
0.694
Dyslipidemia
37 (57.8)
38 (59.4)
0.858
Family history
22 (34.4)
17 (26.6)
0.337
Chronic renal failure
6 (9.4)
3 (4.7)
0.300
Total stent length
53.0 ± 30.2
54.2 ± 40.5
0.851
Stent length [30 mm
48 (75.0)
39 (60.9)
0.088
All-cause death, n (%)
0/56 (0.0)
9/64 (14.1)
0.004
MACE, n (%)a
7/56 (12.5)
23/64 (35.9)
0.003
Diagnosis
0.723
Follow-up data
Data in table are expressed as frequency (%), median (IR) or mean ± SD when appropriate a
MACE = UA, NSTEMI, STEMI, ictus/TIA, cardiac death, target vessel revascularization
* p \ 0.05, ** p \ 0.001
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Intern Emerg Med
study, several HPR patients were switched to these novel antiplatelets. So, at variance with GRAVITAS in which HPR patients were randomized to clopidogrel 75 mg/die vs. 150 mg/die, we had multiple patterns of tailored DAPT (ticlopidine, clopidogrel 150 mg/die, prasugrel or ticagrelor). Moreover, in 32 patients, we also increased the mean daily dosage of acetylsalicylic acid, when HPR by AA was detected, and if not contraindicated, an approach not adopted in GRAVITAS trial in which aspirin treatment was used at a dose of 75–162 mg daily. Finally, at variance with GRAVITAS, we used LTA by ADP instead of verifyNow P2Y12 test for tailoring DAPT. In line with this, are the results of RECLOSE-2 ACS registry that find a more than twofold higher risk for allcause death, myocardial infarction, stent thrombosis or stroke in HPR patients despite up-titrating the dose of clopidogrel [27]. In ARCTIC [26], only 11 % of patients were treated with an alternative antiplatelet drug such as prasugrel, and again the majority of patients were treated with an increased dosage of clopidogrel or with an additional use of glycoprotein IIb/IIIa inhibitors. Finally, it was calculated that the number of patients enrolled in ARCTIC was insufficient to adequately answer the question if a strategy based on laboratory monitoring is better than a standard strategy [26]. On the other hand, a recent metanalysis by Aradi et al. [27] demonstrates that intensifying antiplatelet therapy on the basis of a platelet reactivity test reduces cardiovascular mortality and stent thrombosis after PCI with the net benefit of this approach. In this study, the authors report the use only of double-dose clopidogrel or prasugrel. More recently, in another study on ACS patients, they demonstrate that switching HPR patients to prasugrel reduces thrombotic and bleeding events to a level similar to those without HPR, while switching to double-dose clopidogrel results in higher risk for both thrombotic and bleeding events [28]. Also our data reporting the experience with ticagrelor are in line with these results. In our study, we confirm that about 27 % of patients undergoing PCI show HPR on DAPT, and we have treated them by modifying the antiplatelet treatment to effectively reduce the high platelet reactivity. Indeed, in all patients, we demonstrate the absence of HPR after antiplatelet therapy variation. We find that the risk of patients with initial HPR becomes similar to that of patients with an adequate platelet inhibition. Indeed in our patients, we do not find differences in terms of thrombotic complications at follow-up between patients without HPR and those who reached adequate platelet reactivity after shifting. Moreover, when compared with a propensity score-matched cohort of HPR patients not treated with a shifting therapy,
123
HPR patients treated with a tailored dual antiplatelet regimen exhibit a significantly lower rate of MACE and deaths at follow-up. These results suggest the efficacy of the tailored antiplatelet treatment. In our study, we observe a significant reduction in the degree of platelet inhibition, especially with the use of newer antiplatelet drugs. In particular, the use of ticagrelor determines a significantly greater reduction in residual platelet reactivity with a more predictable effect. This result might be explained by the fact that the resistance to clopidogrel driven by genetic mutations cannot be completely overcome by doubling the clopidogrel dose or switching to prasugrel, which differently from ticagrelor, is a prodrug and shares cytochromes with clopidogrel for its metabolic activation. However, whether the improvement in outcome of our patients was determined by a reduction in HPR or by the use of newer antiplatelet drugs itself, associated per se with a reduction of cardiovascular events, is difficult to establish. Our study demonstrates that HPR patients can benefit from a tailored antiplatelet approach. Interestingly, in our study, as previously demonstrated, HPR is associated with greater total stent length and diabetes suggesting that patients with more severe coronary artery disease may further benefit from a strategy based on a tailored antiplatelet therapy. A limitation of our study is the low number of patients enrolled for which this study is underpowered to reliably detect differences in the occurrence of major adverse cardiovascular events, especially considering the size of the GRAVITAS and ARCTIC trials. In particular, the propensity-matched analysis critically reduced the total number of patients enrolled so these results should be interpreted cautiously. Another study limitation is that this is not a randomized trial. Moreover, in our study, patients with stable CAD were enrolled, for whom data on newer antiplatelet drugs efficacy are not available. In conclusion, these results mirror a real-world experience in which we tailored our antiplatelet treatment on platelet function test in high-risk cardiovascular patients. The lack of an increased risk of bleeding at follow-up suggests that this approach is safe. Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.
Intern Emerg Med
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