- Email: [email protected]
Platelet reactivity in MitraClip patients
VPH-06238; No of Pages 6 Vascular Pharmacology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph
Platelet reactivity in MitraClip patients Amin Polzin ⁎, Shazia Afzal, Jan Balzer, Tienush Rassaf, Malte Kelm, Tobias Zeus Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Düsseldorf, Düsseldorf, Germany
a r t i c l e
i n f o
Article history: Received 5 May 2015 Received in revised form 21 June 2015 Accepted 2 July 2015 Available online xxxx Keywords: MitraClip Aspirin Clopidogrel High on-treatment platelet reactivity
a b s t r a c t Background: Common complications during MitraClip procedure are bleeding and ischemic events. The right strategy of platelet inhibition is unknown and challenging, as there are substantial interindividual responsevariabilities to antiplatelet drugs and additionally, many MitraClip patients are on permanent oral anticoagulation because of atrial fibrillation. We aimed to investigate the incidence of (i) high- and low ontreatment platelet reactivity (HTPR, LTPR) to antiplatelet medication and (ii) clinical complications in MitraClip patients. Methods: In an observational single-center cohort study we investigated 73 patients who underwent MitraClip implantation. Clopidogrel effects were measured using the vasodilator-stimulated protein phosphorylation (VASP) assay, aspirin effects by light-transmission aggregometry (LTA). Clinical complications were investigated during six-month follow-up. Results: HTPR to clopidogrel was observed in 44 patients, LTPR to clopidogrel in 6 patients. 16 patients had HTPR to aspirin. Major complications occurred in 12 patients, overall bleeding complications in 27 patients, overall ischemic events in two patients. The incidence of HTPR/LTPR did not differ between patients with- vs. without clinical complications. Bleeding complications were not more frequent in patients with additional oral anticoagulation. Conclusions: In this study, the incidence of HTPR to clopidogrel was very high (60% of patients). Despite these insufficient clopidogrel antiplatelet effects, ischemic events were rare and bleeding complications more frequent. Additionally, many patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. The optimal antithrombotic regiment should be investigated in large scale clinical trials under consideration of the high incidence of HTPR to clopidogrel medication in MitraClip patients. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Since its introduction, more than 11,000 patients with severe mitral valve regurgitation and high surgical risk underwent MitraClip procedure. The ideal antithrombotic regiment in interventional valve procedures is still not known and challenging, as common periinterventional complications are ischemic events as well as vascular and bleeding complications [1]. The optimal regiment in patients undergoing MitraClip procedure is even more complex as many of the patients suffer from atrial fibrillation [2] and receive permanent oral anticoagulation. At the Abbreviations: CAD, coronary artery disease; HTPR, high on-treatment platelet reactivity; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; LTA, light transmission aggregometry; LTPR, low on-treatment platelet reactivity; PRI, platelet reactivity index; VASP, vasodilator stimulated protein phosphorylation. ⁎ Corresponding author at: Klinik für Kardiologie, Pneumologie und Angiologie, Moorenstrasse 5, 40225 Düsseldorf, Germany. E-mail address: [email protected] (A. Polzin).
moment, no data regarding the optimal regiment exist at all [3]. Despite this lack of evidence, a combination of aspirin and clopidogrel is recommended early after procedure, as applied in prior clinical trials [2,4]. Additionally, the continuation of oral anticoagulation after MitraClip procedure in patients with atrial fibrillation is recommended as well [5]. It is known that there are relevant inter-individual response variabilities especially to clopidogrel antiplatelet medication. Insufficient clopidogrel antiplatelet effects are called high on-treatment platelet reactivity (HTPR) and are associated with ischemic events. Low on-treatment platelet reactivity (LTPR) to clopidogrel medication correlates with bleeding events in patients with coronary artery disease (CAD) [6]. HTPR to aspirin has been shown to increase the incidence of major adverse cardiac events in CAD patients as well [7]. Therefore, in the present study we investigated the antiplatelet effects of clopidogrel and aspirin as well as the incidence of death, ischemic- and bleeding events during hospital stay and at six month follow-up in patients undergoing MitraClip procedure. We aimed to investigate the relation between clinical complications with (i) the incidence of HTPR/LTPR
http://dx.doi.org/10.1016/j.vph.2015.07.015 1537-1891/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
2
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
to antiplatelet medication, and (ii) the incidence of additional oral anticoagulation due to atrial fibrillation. 2. Materials and methods 2.1. Patients From 2010 till 2013, data from 73 patients with severe mitral regurgitation undergoing MitraClip procedure (Abbott, Illinois, USA) at the University Hospital Düsseldorf, Germany, had been analyzed. Eligibility for MitraClip procedure was determined as previously described [8]. Prior to intervention, all patients had been discussed in a ‘heart team’ consisting of cardiologists and cardiovascular surgeons to define the optimal therapeutic strategy (MitraClip vs. surgical repair vs. medical therapy).
2.6. Clinical complications Major complication was defined as death, myocardial infarction, major vascular complications, life threatening/major bleeding, and major stroke. Overall bleeding and ischemic complications were defined using the updated Valve Academic Research Consortium (VARC-2) provided standardized definitions [15]. The bleeding risk of patients was evaluated using the HAS-BLED Score [16]. Follow-up was conducted six months after MitraClip implantation. During hospital course and follow-up visit, transthoracic echocardiography was performed in all patients. In eleven patients with insufficient transthoracic quality, transesophageal echocardiography was used to evaluate position and potential thrombus formation of the MitraClip. 2.7. Statistical analyses
2.2. Study design An observational monocentric real world cohort study was conducted. Eligibility criteria were MitraClip procedure, age above 18 years and informed consent. Exclusion criteria were known thrombocytopathias. Clinical six-month follow-up visits were conducted to investigate the incidence of adverse events. The study was approved by the ethics committee of the Heinrich-Heine University Düsseldorf. Written informed consent was obtained from all participants. 2.3. MitraClip procedure MitraClip procedure was technically conducted as previously described [9]. The used eight French delivery system was withdrawn manually without a vascular closing device. The skin was sealed by a ‘figure-of-eight’-suture. 2.4. Periinterventional antiplatelet/anticoagulation regiment Loading doses of 300 mg clopidogrel and 500 mg aspirin have been administered in clopidogrel and aspirin naïve patients, respectively 12 h prior to intervention. Aspirin 100 mg per day and clopidogrel 75 mg per day were used as maintenance doses, starting at the day of intervention. Already ongoing antiplatelet medication was continued throughout hospital course. In patients with atrial fibrillation, oral anticoagulation had been paused at least 5 days prior to MitraClip procedure. Bridging to intervention was conducted with unfractionated and low-molecular weight heparin depending on renal function. Unfractionated heparin was used for anticoagulation during MitraClip procedure to achieve activated clotting time between 250–300 s. Continuation of oral anticoagulation was started two days post-intervention at the earliest. 2.5. Platelet function analyses Platelet function tests were conducted after MitraClip procedure during hospital course. Blood sampling using a 21 G needle was conducted 2 h after aspirin and clopidogrel intake. The clopidogrel antiplatelet effects were investigated by the pharmacologically most specific test, the vasodilator-stimulated protein phosphorylation (VASP) assay [10]. Cut-off values to define HTPR/LTPR to clopidogrel were applied as recommended by the consensus paper of the Working Group of On-Treatment Platelet Reactivity [6]. Platelet reactivity index (PRI) N 50 was defined as HTPR, PRI b 16% as LTPR. Aspirin effects were evaluated by light-transmission aggregometry. Platelet aggregation was induced by arachidonic acid to allow specific determination of aspirin antiplatelet effects [11]. HTPR was set as maximum of aggregation N 20%. This cut-off value was chosen according to current medical literature. Different studies described an association of HTPR to aspirin and impaired clinical outcome in CAD patients using this cut-off value [12–14]. Screening of 30 in-house samples per assay was used to establish laboratory norms.
Data were analyzed using GraphPad Prism© (La Jolla, USA) and the IBM SPSS© software (New York, USA). Data are mean ± SD. Confidence intervals of 95% were used to assess significance. No outliers have been removed, no data transformation has been conducted, data of patients were complete and no patient was lost to follow-up. Normality of data distribution has been tested by histograms and q–q plots. The unpaired Student's t-test was used to compare continuous variables in case of Gaussian distribution, Mann–Whitney test in non-normally distributed continuous variables. Binary variables were analyzed by the Chi-squared test. Relative risk was calculated according to Altman. 3. Results 3.1. Patients Patients were 73 ± 10 years of age, 49 (67%) were of male gender. 51 patients (70%) suffered of congestive heart failure and 51 patients (70%) had coronary artery disease. Comorbidities and co-medication are outlined in Table 1. 15 (21%) patients presented a functional mitral regurgitation and 58 (79%) patients a degenerative mitral regurgitation. MitraClip procedure was successful in 73 patients (100%) with reduction of mitral valve regurgitation. No conversion to surgery or reintervention had to be performed (Table 1). 3.2. Complications Major complications (death, myocardial infarction, major vascular complications, life threatening/major bleeding, major stroke) occurred in twelve patients (16%). One major complication was observed during hospital course and eleven during follow-up. One patient died subsequent to a hematothorax induced by a pleurocentesis because of pleural effusion during hospital course. One patient died consecutively to a stroke within the follow-up. Additionally, one patient died of cancer and one of sepsis. One acute coronary syndrome with percutaneous coronary intervention occurred during follow-up. No thrombus formation on the MitraClip device occurred at all. Bleeding complications were observed in 27 (37%) patients. 96% (26 patients) bleeding events occurred during hospital course, 4% (one patient) experienced a major bleeding (gastrointestinal) during follow-up. Bleeding during hospital course was predominantly access site related (24 patients; 96%). One gastrointestinal bleeding during hospital stay occurred (Table 2). 3.3. Antiplatelet effects Clopidogrel PRI was 56 ± 25 in MitraClip patients. HTPR to clopidogrel was observed in 44 patients (60%), LTPR to clopidogrel in 6 patients (8%) (Fig. 1/Table 3A). The incidence of HTPR to clopidogrel did not differ between patients with- vs. without additional oral anticoagulation (24 patients [59%] vs. 20 patients [36%]; p = 0.73). Aspirin maximum of aggregation was 18 ± 21%. HTPR to aspirin
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
3
Table 1 Baseline characteristics of the patients. Age (years) Male gender (%)
73 ± 10 49 (67%)
Cause of mitral regurgitation Functional Degenerative
15 (21%) 58 (79%)
Acute procedural success Mitral regurgitation reduction Conversion to surgery Re-intervention
73 (100%) 73 (100%) 0 (0%) 0 (0%)
Congestive heart failure Chronic kidney disease Coronary artery disease Prior myocardial infarction Previous aortocoronary bypass grafting Previous percutaneous coronary intervention Hypertension Hypercholesterolemia Diabetes mellitus COPD
51 (70%) 35 (48%) 51 (70%) 38 (52%) 18 (25%) 36 (49%) 71 (97%) 37 (51%) 23 (32%) 17 (23%)
Aspirin Clopidogrel Oral anticoagulant ACE-/AT1 receptor-inhibitor Beta-blocker Calcium channel blocker Diuretic Aldosterone antagonist Cardiac glycoside Proton-pump inhibitor Statin Oral antidiabetic Insulin
140 (100%) 140 (100%) 41 (56%) 60 (82%) 66 (90%) 12 (16%) 68 (93%) 40 (55%) 17 (23%) 49 (67%) 37 (51%) 10 (14%) 10 (14%)
ACE = angiotensin converting enzyme; AT1 = angiotensin 1; COPD = chronic obstructive lung disease.
occurred in 16 patients (22%) (Fig. 1/Table 3A). 7 patients (10%) had combined HTPR to aspirin and clopidogrel.
Fig. 1. Platelet reactivity in MitraClip patients. Clopidogrel antiplatelet effects measured by VASP assay platelet reactivity index were 56 ± 25. Aspirin effects measured by lighttransmission aggregometry maximum of aggregation were 18 ± 21%.
with ischemic events, there were no differences regarding the incidence of insufficient antiplatelet effects to clopidogrel and aspirin. HTPR and LTPR to clopidogrel medication did not correlate with the incidence of bleeding events in MitraClip patients. HTPR to aspirin was also not associated with bleeding events (Table 4). 3 patients (43%) with dual HTPR to aspirin and clopidogrel experienced adverse events (1 major vascular complication, 2 minor vascular complications, no ischemic event). The incidence of clinical complications did not differ between patients with- vs. without dual HTPR (3 patients vs. 26 patients, relative risk 1.2, confidence interval 0.5–2.9, p = 0.69). 3.5. Anticoagulation and clinical complications 41 (56%) patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. The incidence of oral anticoagulation did not differ between patients with- in comparison to patients without bleeding complications. The HAS-BLED score, evaluating the individual bleeding risk also did not differ (Table 4B). 4. Discussion
3.4. Antiplatelet effects and clinical complications The incidence of HTPR to clopidogrel- and aspirin medication did not differ between patients with clinical complications in comparison to patients without clinical complications (Table 3B). Likewise, in patients
Table 2 Clinical complications in MitraClip patients.
Table 3 Incidence of HTPR in MitraClip patients. In-hospital
6-Month follow-up A
Patients 73 (100%) Mortality: Cardiac cause of death Bleeding Stroke Sepsis Cancer Unknown Ischemic complications: Peri-procedural myocardial infarction Major stroke Minor stroke Transient ischemic attack Thrombus on MitraClip Bleeding complications: Life threatening bleeding Major bleeding Minor bleeding Major vascular complications Minor vascular complications
The major findings of this study are: (i) the incidence of insufficient antiplatelet effects of clopidogrel is very frequent in investigated MitraClip patients, (ii) ischemic complications are rare, bleeding complications more frequent, (iii) the incidence of insufficient antiplatelet effects does not correlate with clinical complications and (iv) need of
1 (1.4%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 26 (36%) 1 (1.4%) 0 (0%) 1 (1.4%) 5 (6.8%) 19 (26%)
73 (100%) 4 (5.5%) 0 (0.0%) 0 (0.0%) 1 (25%) 1 (25%) 1 (25%) 1 (25%) 2 (2.7%) 1 (1.4%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
73 MitraClip procedures
Clopidogrel (VASP)
Aspirin (LTA)
Patients n (%)
HTPR (PRI N 50) 44 (60%) LTPR (PRI b 16) 6 (8%)
HTPR (Aggregation N 20%) 16 (22%)
B 73 MitraClip procedures
Major-complications
No-complications
n (%)
12 (16%)
61 (84%)
61 ± 20 9 (75%) 1.14 (0.79–1.66)
56 ± 26 40 (66%)
0.52 0.52 0.70
20 ± 26 2 (17%) 0.73 (0.2–2.8)
18 ± 22 14 (23%)
0.77 0.63 0.47
Clopidogrel: Mean ± SD HTPR n (%) Relative risk Aspirin: Mean ± SD HTPR n (%) Relative risk
P-value
LTA = light transmission aggregometry; PRI = platelet reactivity index; VASP = vasodilator stimulated protein phosphorylation.
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
4
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
Table 4 Incidence of HTPR in patients with (A) ischemic and (B) bleeding events. A 73 MitraClip procedures
Ischemic events
No-ischemic events
n (%)
2 (3%)
71 (97%)
49 ± 31 1 (50%) 0.65 (0.04–10.1)
57 ± 25 43 (61%)
0.64 0.76 0.76
9 ± 0.7 0 (0%) 0.74 (0.04–14.6)
18 ± 22 15 (21%)
0.55 0.47 0.84
73 MitraClip procedures
Bleeding events
No-bleeding events
P-value
n (%)
27 (37%)
46 (63%)
59 ± 22 18 (67%) 1.17 (0.81–1.7) 1 (4%) 0.34 (0.04–2.76)
56 ± 27 26 (57%)
Clopidogrel: Mean ± SD HTPR n (%) Relative risk Aspirin: Mean ± SD HTPR n (%) Relative risk
P-value
B
Clopidogrel: Mean ± SD HTPR n (%) Relative risk LTPR n (%) Relative risk Aspirin: Mean ± SD HTPR n (%) Relative risk
14 ± 18 5 (19%)
5 (11%)
20 ± 23 10 (22%)
0.65 0.39 0.38 0.28 0.31 0.29 0.74. 0.74
0.85 (0.32–2.23) Oral anticoagulation: 17 (63%)
24 (52%)
Relative risk
0.37 0.92
1.21 (0.8–1.8) HAS-BLED-Score 2.7 ± 0.7
2.4 ± 0.8
0.35
additional oral anticoagulation besides antiplatelet medication is not associated with the incidence of bleeding events. The incidence of HTPR to clopidogrel (44 patients; 60%) was high in investigated MitraClip patients (Table 3A). Occurrence of HTPR to clopidogrel varies between different platelet function assays. A metaanalysis by Mallouk et al. reported HTPR to clopidogrel in 20.6% of patients measured by light-transmission aggregometry, 33.5% patients measured by the VerifyNow assay and in 49.5% of patients measured by the VASP assay [17]. In this study, the VASP assay was applied as it is the pharmacologically most specific test to investigate P2Y12 inhibition by clopidogrel [10]. Overall, the incidence of HTPR in patients with CAD was described to vary from 5–50% [7,17]. Focusing on recent studies applying the VASP assay, Cuisset et al. reported HTPR to clopidogrel in 34% of CAD patients; [18] Darlington et al. in 45% of CAD patients [19]. In both studies, patients tended to be younger as compared to investigated MitraClip patients (64 ± 12 years/54.45 ± 7.8 years vs. 73 ± 10 years). In the present study, occurrence of diabetes mellitus was similar in comparison to the study by Cuisset et al. (32% of patients vs. 31% of patients), but more frequent as compared to the study by Darlington et al. which excluded diabetic patients. Multiple reasons for HTPR to clopidogrel have been described, including genetic factors, stress, drug–drug interactions and diabetes mellitus [20]. Furthermore, age has been shown to be associated with impaired response to clopidogrel [21]. As mentioned, the investigated patients undergoing MitraClip procedure were elderly, polymorbid and polymedicated as in this observational study only patients with high surgical risk underwent MitraClip procedure (Table 1). Therefore this might be a reason for the observed high incidence of HTPR in MitraClip patients. Additionally, the loading dose of clopidogrel affects the rate of HTPR. A loading dose of 600 mg was described to achieve sufficient clopidogrel antiplatelet effects more frequently (87–95%) than a 300 mg loading dose (77–66%) [7]. Furthermore, a 600 mg loading dose results in a more rapid onset of platelet inhibition, therefore this high loading dose is
recommended in acute coronary syndromes with indication for urgent percutaneous coronary intervention [22]. However, an increased incidence of bleeding has been described in patients receiving 600 mg clopidogrel loading dose [23]. To date, 300 mg clopidogrel remains the recommended dose in planned percutaneous coronary interventions [22]. No data investigating the optimal loading dose in patients with non-coronary cardiac interventions exist. In this study, MitraClip procedure was planned; patients were elderly, polymorbid and on a high bleeding risk. Therefore a loading dose of 300 mg clopidogrel was chosen. In patients without additional oral anticoagulation, a loading dose of 600 mg could be an alternative, especially as we observed a high incidence of HTPR to clopidogrel. However on the other hand, no ischemic event during hospital course was registered, but several bleeding events. Therefore, the optimal loading dose and antiplatelet regiment remain unclear. In this study, HTPR to aspirin occurred in 16 (22%) patients (Table 3A). This incidence is similar to previously described data. A systematical review of studies investigating the frequency of insufficient antiplatelet effects of aspirin described the prevalence to be 24% [24]. Likewise to clopidogrel insufficient effects, factors for HTPR to aspirin are multifactorial. Variable bioavailability, enhanced aspirin degradation, genetic polymorphism of cyclooxygenase, cyclooxygenase-2 mediated thromboxane formation, and drug–drug interactions may be responsible for insufficient aspirin antiplatelet effects [25,26]. Bleeding complications are more frequent than ischemic events in patients undergoing MitraClip procedure. In this study, 27 (37%) patients experienced a bleeding complication (Table 2). The incidence of bleeding complications described in the EVEREST II trial was 13% [2]. However, bleeding complications in the EVERST II trial were defined as transfusion of ≥ 2 U of blood. Minor bleedings and minor vascular complications were not included. Therefore, as in the present study we also considered minor bleedings and minor vascular complications according to the VARC-2 provided standardized definition of clinical complications, it does not surprise, that overall bleeding complications were higher [15]. In our study, major bleedings/vascular complications (transfusion of ≥2 U of blood) accounted for only 8.2% of bleeding complications. Most minor vascular complications were access site related (24 of 27 patients). Ischemic events were rare. There were no ischemic events during hospital course at all. During follow up, one stroke and one acute coronary syndrome occurred (Table 2). Both patients had sufficient aspirin antiplatelet effects; one patient had insufficient clopidogrel antiplatelet effects (Table 4A). However the subgroup is too small to allow reasonable analysis. There were no differences regarding the incidence of HTPR/LTPR to clopidogrel and HTPR to aspirin between patients with- and without bleeding complications (Table 4B). Previously, a correlation between LTPR to clopidogrel and bleeding has been described [6]. However, in our study, the incidence of LTPR was low (six patients). Due to small sample size, it was not surprising, that we were not able to correlate LTPR and bleeding events. Furthermore, the incidence of additional oral anticoagulation also did not differ between patients with- and without bleeding complications. As most of the bleeding complications were access site related and oral anticoagulation was paused periinterventional, this was not surprising at all. At the moment, dual antiplatelet therapy is applied early after MitraClip procedure [2,4]. Existing permanent oral anticoagulation is recommended to be continued as well [5]. In this study, the incidence of HTPR to clopidogrel was very high. Despite that, ischemic complications were rare and bleeding events more frequent. Therefore, one could hypothesize, that single antiplatelet medication with aspirin might be enough. However, alternatively it could be hypothesized that platelet function testing does not add value to predict outcome, as despite being underpowered the association between HTPR and adverse events was not even borderline significant in this study. This would go in line with results of recent trials that failed to improve outcome of CAD patients by tailoring antiplatelet therapy according to results of
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
platelet function assays [27–29]. However, all trials had limitations regarding study design which might partially have led to its negative results [30]. Contradictory, three smaller trials were able to demonstrate, that tailoring antiplatelet therapy is able to improve outcome [31–33]. Moreover, many trials demonstrated an association between HTPR and clinical outcome [6,12–14,34,35]. Therefore, large clinical trials are needed to clarify the situation and investigate the optimal antithrombotic regiment in MitraClip patients. 5. Conclusion In conclusion, the incidence of HTPR to clopidogrel medication is very high. However ischemic events were rare and bleeding events more frequent. Additionally, many patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. This finding underlines the need of large scale clinical trials to assess the optimal antiplatelet/anticoagulation regiment in MitraClip patients. These trials should take the high incidence of HTPR to clopidogrel into account and monitor antiplatelet effects accurately. 6. Study limitations We conducted a hypothesis generating pilot study to assess antiplatelet effects of clopidogrel and aspirin in patients undergoing MitraClip procedure. The study was not powered to correlate antiplatelet effects with clinical endpoints. Ethics committee approval The study conformed to the Declaration of Helsinki and was accepted by the University of Düsseldorf Ethics Committee. Source of funding TR is a Heisenberg Professor funded by the German Research Foundation; grant number: DFG RA969/7-2; Grant sponsor: Federal State Government of North Rhine-Westphalia and the European Union (EFRE-Program “Med in.NRW”); grant number: 005-GW01–235A. Disclosures None. Acknowledgments None. References [1] L. Mauri, E. Foster, D.D. Glower, P. Apruzzese, J.M. Massaro, H.C. Herrmann, et al., 4year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation, J. Am. Coll. Cardiol. 62 (4) (2013) 317–328 (Epub 2013/ 05/15). [2] T. Feldman, E. Foster, D.D. Glower, S. Kar, M.J. Rinaldi, P.S. Fail, et al., Percutaneous repair or surgery for mitral regurgitation, N. Engl. J. Med. 364 (15) (2011) 1395–1406 (Epub 2011/04/06). [3] A. Vahanian, O. Alfieri, F. Andreotti, M.J. Antunes, G. Baron-Esquivias, H. Baumgartner, et al., Guidelines on the management of valvular heart disease (version 2012), Eur. Heart J. 33 (19) (2012) 2451–2496 (Epub 2012/08/28). [4] O. Franzen, S. Baldus, V. Rudolph, S. Meyer, M. Knap, D. Koschyk, et al., Acute outcomes of MitraClip therapy for mitral regurgitation in high-surgical-risk patients: emphasis on adverse valve morphology and severe left ventricular dysfunction, Eur. Heart J. 31 (11) (2010) 1373–1381 (Epub 2010/03/12). [5] S. Alsidawi, M. Effat, Peri-procedural management of anti-platelets and anticoagulation in patients undergoing MitraClip procedure, J. Thromb. Thrombolysis 38 (3) (2014) 416–419. [6] U.S. Tantry, L. Bonello, D. Aradi, M.J. Price, Y.H. Jeong, D.J. Angiolillo, et al., Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding, J. Am. Coll. Cardiol. 62 (24) (2013) 2261–2273 (Epub 2013/10/01).
5
[7] P.A. Gurbel, R.C. Becker, K.G. Mann, S.R. Steinhubl, A.D. Michelson, Platelet function monitoring in patients with coronary artery disease, J. Am. Coll. Cardiol. 50 (19) (2007) 1822–1834 (Epub 2007/11/06). [8] T. Rassaf, J. Balzer, T. Zeus, C. Rammos, S. Shayganfar, S.V. Hall, et al., Safety and efficacy of deep sedation as compared to general anaesthesia in percutaneous mitral valve repair using the MitraClip(R) systemOfficial Journal of the Society for Cardiac Angiography & Interventions Catheter. Cardiovasc. Interv. 84 (4) (2014) E38–E42 (Epub 2014/06/10). [9] T. Feldman, S. Kar, M. Rinaldi, P. Fail, J. Hermiller, R. Smalling, et al., Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort, J. Am. Coll. Cardiol. 54 (8) (2009) 686–694 (Epub 2009/08/15). [10] T. Garabedian, S. Alam, High residual platelet reactivity on clopidogrel: its significance and therapeutic challenges overcoming clopidogrel resistance, Cardiovasc. Diagn. Ther. 3 (1) (2013) 23–37 (Epub 2013/11/28). [11] K. Schror, K. Huber, T. Hohlfeld, Functional testing methods for the antiplatelet effects of aspirin, Biomark. Med. 5 (1) (2011) 31–42 (Epub 2011/02/16). [12] P.A. Gum, K. Kottke-Marchant, P.A. Welsh, J. White, E.J. Topol, A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease, J. Am. Coll. Cardiol. 41 (6) (2003) 961–965 (Epub 2003/03/ 26). [13] N.J. Breet, J.W. van Werkum, H.J. Bouman, J.C. Kelder, J.M. Ten Berg, C.M. Hackeng, High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events, J. Thromb. Haemost. 8 (10) (2010) 2140–2148 (Epub 2010/08/21). [14] G. Krasopoulos, S.J. Brister, W.S. Beattie, M.R. Buchanan, Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis, BMJ 336 (7637) (2008) 195–198 (Epub 2008/01/19). [15] A.P. Kappetein, S.J. Head, P. Genereux, N. Piazza, N.M. van Mieghem, E.H. Blackstone, et al., Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document, Eur. Heart J. 33 (19) (2012) 2403–2418 (Epub 2012/10/03). [16] R. Pisters, D.A. Lane, R. Nieuwlaat, C.B. de Vos, H.J. Crijns, G.Y. Lip, A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey, Chest 138 (5) (2010) 1093–1100 (Epub 2010/03/20). [17] N. Mallouk, C. Labruyere, J.L. Reny, C. Chapelle, M. Piot, P. Fontana, et al., Prevalence of poor biological response to clopidogrel: a systematic review, Thromb. Haemost. 107 (3) (2012) 494–506 (Epub 2012/01/26). [18] T. Cuisset, J. Quilici, P.E. Morange, J.L. Bonnet, M.C. Alessi, Predictors of long-term high on-treatment platelet reactivity in clopidogrel-treated patients undergoing coronary stenting for acute coronary syndrome, Int. J. Cardiol. 168 (2) (2013) 1565–1566 (Epub 2013/01/22). [19] A. Darlington, A. Tello-Montoliu, F. Rollini, M. Ueno, J.L. Ferreiro, R. Patel, et al., Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease, Thromb. Haemost. 111 (2) (2014) 258–265 (Epub 2013/10/25). [20] O. Ait-Mokhtar, L. Bonello, S. Benamara, F. Paganelli, High on treatment platelet reactivity, Heart Lung Circ. 21 (1) (2012) 12–21 (Epub 2011/10/18). [21] J. Silvain, G. Cayla, J.S. Hulot, J. Finzi, M. Kerneis, S.A. O'Connor, et al., High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIORPLATELET study, Eur. Heart J. 33 (10) (2012) 1241–1249 (Epub 2011/11/10). [22] J. Silvain, A. Bellemain-Appaix, O. Barthelemy, F. Beygui, J.P. Collet, G. Montalescot, Optimal use of thienopyridines in non-ST-elevation acute coronary syndrome following CURRENT-OASIS 7, Circ. Cardiovasc. Interv. 4 (1) (2011) 95–103 (Epub 2011/02/18). [23] N.L. Cruden, K. Morch, D.R. Wong, W.P. Klinke, J. Ofiesh, J.D. Hilton, Clopidogrel loading dose and bleeding outcomes in patients undergoing urgent coronary artery bypass grafting, Am. Heart J. 161 (2) (2011) 404–410 (Epub 2011/02/15). [24] M.M. Hovens, J.D. Snoep, J.C. Eikenboom, J.G. van der Bom, B.J. Mertens, M.V. Huisman, Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review, Am. Heart J. 153 (2) (2007) 175–181 (Epub 2007/01/24). [25] T. Hohlfeld, A. Saxena, K. Schror, High on treatment platelet reactivity against aspirin by non-steroidal anti-inflammatory drugs — pharmacological mechanisms and clinical relevance, Thromb. Haemost. 109 (5) (2013) 825–833 (Epub 2012/12/15). [26] A. Polzin, T. Zeus, K. Schror, M. Kelm, T. Hohlfeld, Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease, J. Am. Coll. Cardiol. 62 (18) (2013) 1725–1726 (Epub 2011/03/17). [27] M.J. Price, P.B. Berger, P.S. Teirstein, J.F. Tanguay, D.J. Angiolillo, D. Spriggs, et al., Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial, JAMA 305 (11) (2011) 1097–1105 (Epub 2011/03/17). [28] G. Montalescot, G. Range, J. Silvain, J.L. Bonnet, Z. Boueri, O. Barthelemy, et al., High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: a landmark analysis of the ARCTIC study, Circulation 129 (21) (2014) 2136–2143 (Epub 2014/04/11). [29] D. Trenk, G.W. Stone, M. Gawaz, A. Kastrati, D.J. Angiolillo, U. Muller, et al., A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study, J. Am. Coll. Cardiol. 59 (24) (2012) 2159–2164 (Epub 2012/04/24). [30] J.M. Siller-Matula, B. Jilma, Why have studies of tailored anti-platelet therapy failed so far? Thromb. Haemost. 110 (4) (2013) 628–631 (Epub 2013/07/26).
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
6
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
[31] L. Bonello, L. Camoin-Jau, S. Armero, O. Com, S. Arques, C. Burignat-Bonello, et al., Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis, Am. J. Cardiol. 103 (1) (2009) 5–10 (Epub 2008/12/23). [32] L. Bonello, L. Camoin-Jau, S. Arques, C. Boyer, D. Panagides, O. Wittenberg, et al., Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study, J. Am. Coll. Cardiol. 51 (14) (2008) 1404–1411 (Epub 2008/04/05). [33] T. Cuisset, C. Frere, J. Quilici, P.E. Morange, J.P. Mouret, L. Bali, et al., Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders:
a prospective, randomized study, J. Am. Coll. Cardiol. Intv. 1 (6) (2008) 649–653 (Epub 2009/05/26). [34] N.J. Breet, J.W. van Werkum, H.J. Bouman, J.C. Kelder, H.J. Ruven, E.T. Bal, et al., Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation, JAMA 303 (8) (2010) 754–762 (Epub 2010/02/25). [35] K. Mayer, I. Bernlochner, S. Braun, S. Schulz, M. Orban, T. Morath, et al., Aspirin treatment and outcomes after percutaneous coronary intervention: results of the ISARASPI registry, J. Am. Coll. Cardiol. 64 (9) (2014) 863–871 (Epub 2014/08/30).
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
Contents lists available at ScienceDirect
Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph
Platelet reactivity in MitraClip patients Amin Polzin ⁎, Shazia Afzal, Jan Balzer, Tienush Rassaf, Malte Kelm, Tobias Zeus Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Düsseldorf, Düsseldorf, Germany
a r t i c l e
i n f o
Article history: Received 5 May 2015 Received in revised form 21 June 2015 Accepted 2 July 2015 Available online xxxx Keywords: MitraClip Aspirin Clopidogrel High on-treatment platelet reactivity
a b s t r a c t Background: Common complications during MitraClip procedure are bleeding and ischemic events. The right strategy of platelet inhibition is unknown and challenging, as there are substantial interindividual responsevariabilities to antiplatelet drugs and additionally, many MitraClip patients are on permanent oral anticoagulation because of atrial fibrillation. We aimed to investigate the incidence of (i) high- and low ontreatment platelet reactivity (HTPR, LTPR) to antiplatelet medication and (ii) clinical complications in MitraClip patients. Methods: In an observational single-center cohort study we investigated 73 patients who underwent MitraClip implantation. Clopidogrel effects were measured using the vasodilator-stimulated protein phosphorylation (VASP) assay, aspirin effects by light-transmission aggregometry (LTA). Clinical complications were investigated during six-month follow-up. Results: HTPR to clopidogrel was observed in 44 patients, LTPR to clopidogrel in 6 patients. 16 patients had HTPR to aspirin. Major complications occurred in 12 patients, overall bleeding complications in 27 patients, overall ischemic events in two patients. The incidence of HTPR/LTPR did not differ between patients with- vs. without clinical complications. Bleeding complications were not more frequent in patients with additional oral anticoagulation. Conclusions: In this study, the incidence of HTPR to clopidogrel was very high (60% of patients). Despite these insufficient clopidogrel antiplatelet effects, ischemic events were rare and bleeding complications more frequent. Additionally, many patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. The optimal antithrombotic regiment should be investigated in large scale clinical trials under consideration of the high incidence of HTPR to clopidogrel medication in MitraClip patients. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Since its introduction, more than 11,000 patients with severe mitral valve regurgitation and high surgical risk underwent MitraClip procedure. The ideal antithrombotic regiment in interventional valve procedures is still not known and challenging, as common periinterventional complications are ischemic events as well as vascular and bleeding complications [1]. The optimal regiment in patients undergoing MitraClip procedure is even more complex as many of the patients suffer from atrial fibrillation [2] and receive permanent oral anticoagulation. At the Abbreviations: CAD, coronary artery disease; HTPR, high on-treatment platelet reactivity; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; LTA, light transmission aggregometry; LTPR, low on-treatment platelet reactivity; PRI, platelet reactivity index; VASP, vasodilator stimulated protein phosphorylation. ⁎ Corresponding author at: Klinik für Kardiologie, Pneumologie und Angiologie, Moorenstrasse 5, 40225 Düsseldorf, Germany. E-mail address: [email protected] (A. Polzin).
moment, no data regarding the optimal regiment exist at all [3]. Despite this lack of evidence, a combination of aspirin and clopidogrel is recommended early after procedure, as applied in prior clinical trials [2,4]. Additionally, the continuation of oral anticoagulation after MitraClip procedure in patients with atrial fibrillation is recommended as well [5]. It is known that there are relevant inter-individual response variabilities especially to clopidogrel antiplatelet medication. Insufficient clopidogrel antiplatelet effects are called high on-treatment platelet reactivity (HTPR) and are associated with ischemic events. Low on-treatment platelet reactivity (LTPR) to clopidogrel medication correlates with bleeding events in patients with coronary artery disease (CAD) [6]. HTPR to aspirin has been shown to increase the incidence of major adverse cardiac events in CAD patients as well [7]. Therefore, in the present study we investigated the antiplatelet effects of clopidogrel and aspirin as well as the incidence of death, ischemic- and bleeding events during hospital stay and at six month follow-up in patients undergoing MitraClip procedure. We aimed to investigate the relation between clinical complications with (i) the incidence of HTPR/LTPR
http://dx.doi.org/10.1016/j.vph.2015.07.015 1537-1891/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
2
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
to antiplatelet medication, and (ii) the incidence of additional oral anticoagulation due to atrial fibrillation. 2. Materials and methods 2.1. Patients From 2010 till 2013, data from 73 patients with severe mitral regurgitation undergoing MitraClip procedure (Abbott, Illinois, USA) at the University Hospital Düsseldorf, Germany, had been analyzed. Eligibility for MitraClip procedure was determined as previously described [8]. Prior to intervention, all patients had been discussed in a ‘heart team’ consisting of cardiologists and cardiovascular surgeons to define the optimal therapeutic strategy (MitraClip vs. surgical repair vs. medical therapy).
2.6. Clinical complications Major complication was defined as death, myocardial infarction, major vascular complications, life threatening/major bleeding, and major stroke. Overall bleeding and ischemic complications were defined using the updated Valve Academic Research Consortium (VARC-2) provided standardized definitions [15]. The bleeding risk of patients was evaluated using the HAS-BLED Score [16]. Follow-up was conducted six months after MitraClip implantation. During hospital course and follow-up visit, transthoracic echocardiography was performed in all patients. In eleven patients with insufficient transthoracic quality, transesophageal echocardiography was used to evaluate position and potential thrombus formation of the MitraClip. 2.7. Statistical analyses
2.2. Study design An observational monocentric real world cohort study was conducted. Eligibility criteria were MitraClip procedure, age above 18 years and informed consent. Exclusion criteria were known thrombocytopathias. Clinical six-month follow-up visits were conducted to investigate the incidence of adverse events. The study was approved by the ethics committee of the Heinrich-Heine University Düsseldorf. Written informed consent was obtained from all participants. 2.3. MitraClip procedure MitraClip procedure was technically conducted as previously described [9]. The used eight French delivery system was withdrawn manually without a vascular closing device. The skin was sealed by a ‘figure-of-eight’-suture. 2.4. Periinterventional antiplatelet/anticoagulation regiment Loading doses of 300 mg clopidogrel and 500 mg aspirin have been administered in clopidogrel and aspirin naïve patients, respectively 12 h prior to intervention. Aspirin 100 mg per day and clopidogrel 75 mg per day were used as maintenance doses, starting at the day of intervention. Already ongoing antiplatelet medication was continued throughout hospital course. In patients with atrial fibrillation, oral anticoagulation had been paused at least 5 days prior to MitraClip procedure. Bridging to intervention was conducted with unfractionated and low-molecular weight heparin depending on renal function. Unfractionated heparin was used for anticoagulation during MitraClip procedure to achieve activated clotting time between 250–300 s. Continuation of oral anticoagulation was started two days post-intervention at the earliest. 2.5. Platelet function analyses Platelet function tests were conducted after MitraClip procedure during hospital course. Blood sampling using a 21 G needle was conducted 2 h after aspirin and clopidogrel intake. The clopidogrel antiplatelet effects were investigated by the pharmacologically most specific test, the vasodilator-stimulated protein phosphorylation (VASP) assay [10]. Cut-off values to define HTPR/LTPR to clopidogrel were applied as recommended by the consensus paper of the Working Group of On-Treatment Platelet Reactivity [6]. Platelet reactivity index (PRI) N 50 was defined as HTPR, PRI b 16% as LTPR. Aspirin effects were evaluated by light-transmission aggregometry. Platelet aggregation was induced by arachidonic acid to allow specific determination of aspirin antiplatelet effects [11]. HTPR was set as maximum of aggregation N 20%. This cut-off value was chosen according to current medical literature. Different studies described an association of HTPR to aspirin and impaired clinical outcome in CAD patients using this cut-off value [12–14]. Screening of 30 in-house samples per assay was used to establish laboratory norms.
Data were analyzed using GraphPad Prism© (La Jolla, USA) and the IBM SPSS© software (New York, USA). Data are mean ± SD. Confidence intervals of 95% were used to assess significance. No outliers have been removed, no data transformation has been conducted, data of patients were complete and no patient was lost to follow-up. Normality of data distribution has been tested by histograms and q–q plots. The unpaired Student's t-test was used to compare continuous variables in case of Gaussian distribution, Mann–Whitney test in non-normally distributed continuous variables. Binary variables were analyzed by the Chi-squared test. Relative risk was calculated according to Altman. 3. Results 3.1. Patients Patients were 73 ± 10 years of age, 49 (67%) were of male gender. 51 patients (70%) suffered of congestive heart failure and 51 patients (70%) had coronary artery disease. Comorbidities and co-medication are outlined in Table 1. 15 (21%) patients presented a functional mitral regurgitation and 58 (79%) patients a degenerative mitral regurgitation. MitraClip procedure was successful in 73 patients (100%) with reduction of mitral valve regurgitation. No conversion to surgery or reintervention had to be performed (Table 1). 3.2. Complications Major complications (death, myocardial infarction, major vascular complications, life threatening/major bleeding, major stroke) occurred in twelve patients (16%). One major complication was observed during hospital course and eleven during follow-up. One patient died subsequent to a hematothorax induced by a pleurocentesis because of pleural effusion during hospital course. One patient died consecutively to a stroke within the follow-up. Additionally, one patient died of cancer and one of sepsis. One acute coronary syndrome with percutaneous coronary intervention occurred during follow-up. No thrombus formation on the MitraClip device occurred at all. Bleeding complications were observed in 27 (37%) patients. 96% (26 patients) bleeding events occurred during hospital course, 4% (one patient) experienced a major bleeding (gastrointestinal) during follow-up. Bleeding during hospital course was predominantly access site related (24 patients; 96%). One gastrointestinal bleeding during hospital stay occurred (Table 2). 3.3. Antiplatelet effects Clopidogrel PRI was 56 ± 25 in MitraClip patients. HTPR to clopidogrel was observed in 44 patients (60%), LTPR to clopidogrel in 6 patients (8%) (Fig. 1/Table 3A). The incidence of HTPR to clopidogrel did not differ between patients with- vs. without additional oral anticoagulation (24 patients [59%] vs. 20 patients [36%]; p = 0.73). Aspirin maximum of aggregation was 18 ± 21%. HTPR to aspirin
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
3
Table 1 Baseline characteristics of the patients. Age (years) Male gender (%)
73 ± 10 49 (67%)
Cause of mitral regurgitation Functional Degenerative
15 (21%) 58 (79%)
Acute procedural success Mitral regurgitation reduction Conversion to surgery Re-intervention
73 (100%) 73 (100%) 0 (0%) 0 (0%)
Congestive heart failure Chronic kidney disease Coronary artery disease Prior myocardial infarction Previous aortocoronary bypass grafting Previous percutaneous coronary intervention Hypertension Hypercholesterolemia Diabetes mellitus COPD
51 (70%) 35 (48%) 51 (70%) 38 (52%) 18 (25%) 36 (49%) 71 (97%) 37 (51%) 23 (32%) 17 (23%)
Aspirin Clopidogrel Oral anticoagulant ACE-/AT1 receptor-inhibitor Beta-blocker Calcium channel blocker Diuretic Aldosterone antagonist Cardiac glycoside Proton-pump inhibitor Statin Oral antidiabetic Insulin
140 (100%) 140 (100%) 41 (56%) 60 (82%) 66 (90%) 12 (16%) 68 (93%) 40 (55%) 17 (23%) 49 (67%) 37 (51%) 10 (14%) 10 (14%)
ACE = angiotensin converting enzyme; AT1 = angiotensin 1; COPD = chronic obstructive lung disease.
occurred in 16 patients (22%) (Fig. 1/Table 3A). 7 patients (10%) had combined HTPR to aspirin and clopidogrel.
Fig. 1. Platelet reactivity in MitraClip patients. Clopidogrel antiplatelet effects measured by VASP assay platelet reactivity index were 56 ± 25. Aspirin effects measured by lighttransmission aggregometry maximum of aggregation were 18 ± 21%.
with ischemic events, there were no differences regarding the incidence of insufficient antiplatelet effects to clopidogrel and aspirin. HTPR and LTPR to clopidogrel medication did not correlate with the incidence of bleeding events in MitraClip patients. HTPR to aspirin was also not associated with bleeding events (Table 4). 3 patients (43%) with dual HTPR to aspirin and clopidogrel experienced adverse events (1 major vascular complication, 2 minor vascular complications, no ischemic event). The incidence of clinical complications did not differ between patients with- vs. without dual HTPR (3 patients vs. 26 patients, relative risk 1.2, confidence interval 0.5–2.9, p = 0.69). 3.5. Anticoagulation and clinical complications 41 (56%) patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. The incidence of oral anticoagulation did not differ between patients with- in comparison to patients without bleeding complications. The HAS-BLED score, evaluating the individual bleeding risk also did not differ (Table 4B). 4. Discussion
3.4. Antiplatelet effects and clinical complications The incidence of HTPR to clopidogrel- and aspirin medication did not differ between patients with clinical complications in comparison to patients without clinical complications (Table 3B). Likewise, in patients
Table 2 Clinical complications in MitraClip patients.
Table 3 Incidence of HTPR in MitraClip patients. In-hospital
6-Month follow-up A
Patients 73 (100%) Mortality: Cardiac cause of death Bleeding Stroke Sepsis Cancer Unknown Ischemic complications: Peri-procedural myocardial infarction Major stroke Minor stroke Transient ischemic attack Thrombus on MitraClip Bleeding complications: Life threatening bleeding Major bleeding Minor bleeding Major vascular complications Minor vascular complications
The major findings of this study are: (i) the incidence of insufficient antiplatelet effects of clopidogrel is very frequent in investigated MitraClip patients, (ii) ischemic complications are rare, bleeding complications more frequent, (iii) the incidence of insufficient antiplatelet effects does not correlate with clinical complications and (iv) need of
1 (1.4%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 26 (36%) 1 (1.4%) 0 (0%) 1 (1.4%) 5 (6.8%) 19 (26%)
73 (100%) 4 (5.5%) 0 (0.0%) 0 (0.0%) 1 (25%) 1 (25%) 1 (25%) 1 (25%) 2 (2.7%) 1 (1.4%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 1 (1.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
73 MitraClip procedures
Clopidogrel (VASP)
Aspirin (LTA)
Patients n (%)
HTPR (PRI N 50) 44 (60%) LTPR (PRI b 16) 6 (8%)
HTPR (Aggregation N 20%) 16 (22%)
B 73 MitraClip procedures
Major-complications
No-complications
n (%)
12 (16%)
61 (84%)
61 ± 20 9 (75%) 1.14 (0.79–1.66)
56 ± 26 40 (66%)
0.52 0.52 0.70
20 ± 26 2 (17%) 0.73 (0.2–2.8)
18 ± 22 14 (23%)
0.77 0.63 0.47
Clopidogrel: Mean ± SD HTPR n (%) Relative risk Aspirin: Mean ± SD HTPR n (%) Relative risk
P-value
LTA = light transmission aggregometry; PRI = platelet reactivity index; VASP = vasodilator stimulated protein phosphorylation.
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
4
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
Table 4 Incidence of HTPR in patients with (A) ischemic and (B) bleeding events. A 73 MitraClip procedures
Ischemic events
No-ischemic events
n (%)
2 (3%)
71 (97%)
49 ± 31 1 (50%) 0.65 (0.04–10.1)
57 ± 25 43 (61%)
0.64 0.76 0.76
9 ± 0.7 0 (0%) 0.74 (0.04–14.6)
18 ± 22 15 (21%)
0.55 0.47 0.84
73 MitraClip procedures
Bleeding events
No-bleeding events
P-value
n (%)
27 (37%)
46 (63%)
59 ± 22 18 (67%) 1.17 (0.81–1.7) 1 (4%) 0.34 (0.04–2.76)
56 ± 27 26 (57%)
Clopidogrel: Mean ± SD HTPR n (%) Relative risk Aspirin: Mean ± SD HTPR n (%) Relative risk
P-value
B
Clopidogrel: Mean ± SD HTPR n (%) Relative risk LTPR n (%) Relative risk Aspirin: Mean ± SD HTPR n (%) Relative risk
14 ± 18 5 (19%)
5 (11%)
20 ± 23 10 (22%)
0.65 0.39 0.38 0.28 0.31 0.29 0.74. 0.74
0.85 (0.32–2.23) Oral anticoagulation: 17 (63%)
24 (52%)
Relative risk
0.37 0.92
1.21 (0.8–1.8) HAS-BLED-Score 2.7 ± 0.7
2.4 ± 0.8
0.35
additional oral anticoagulation besides antiplatelet medication is not associated with the incidence of bleeding events. The incidence of HTPR to clopidogrel (44 patients; 60%) was high in investigated MitraClip patients (Table 3A). Occurrence of HTPR to clopidogrel varies between different platelet function assays. A metaanalysis by Mallouk et al. reported HTPR to clopidogrel in 20.6% of patients measured by light-transmission aggregometry, 33.5% patients measured by the VerifyNow assay and in 49.5% of patients measured by the VASP assay [17]. In this study, the VASP assay was applied as it is the pharmacologically most specific test to investigate P2Y12 inhibition by clopidogrel [10]. Overall, the incidence of HTPR in patients with CAD was described to vary from 5–50% [7,17]. Focusing on recent studies applying the VASP assay, Cuisset et al. reported HTPR to clopidogrel in 34% of CAD patients; [18] Darlington et al. in 45% of CAD patients [19]. In both studies, patients tended to be younger as compared to investigated MitraClip patients (64 ± 12 years/54.45 ± 7.8 years vs. 73 ± 10 years). In the present study, occurrence of diabetes mellitus was similar in comparison to the study by Cuisset et al. (32% of patients vs. 31% of patients), but more frequent as compared to the study by Darlington et al. which excluded diabetic patients. Multiple reasons for HTPR to clopidogrel have been described, including genetic factors, stress, drug–drug interactions and diabetes mellitus [20]. Furthermore, age has been shown to be associated with impaired response to clopidogrel [21]. As mentioned, the investigated patients undergoing MitraClip procedure were elderly, polymorbid and polymedicated as in this observational study only patients with high surgical risk underwent MitraClip procedure (Table 1). Therefore this might be a reason for the observed high incidence of HTPR in MitraClip patients. Additionally, the loading dose of clopidogrel affects the rate of HTPR. A loading dose of 600 mg was described to achieve sufficient clopidogrel antiplatelet effects more frequently (87–95%) than a 300 mg loading dose (77–66%) [7]. Furthermore, a 600 mg loading dose results in a more rapid onset of platelet inhibition, therefore this high loading dose is
recommended in acute coronary syndromes with indication for urgent percutaneous coronary intervention [22]. However, an increased incidence of bleeding has been described in patients receiving 600 mg clopidogrel loading dose [23]. To date, 300 mg clopidogrel remains the recommended dose in planned percutaneous coronary interventions [22]. No data investigating the optimal loading dose in patients with non-coronary cardiac interventions exist. In this study, MitraClip procedure was planned; patients were elderly, polymorbid and on a high bleeding risk. Therefore a loading dose of 300 mg clopidogrel was chosen. In patients without additional oral anticoagulation, a loading dose of 600 mg could be an alternative, especially as we observed a high incidence of HTPR to clopidogrel. However on the other hand, no ischemic event during hospital course was registered, but several bleeding events. Therefore, the optimal loading dose and antiplatelet regiment remain unclear. In this study, HTPR to aspirin occurred in 16 (22%) patients (Table 3A). This incidence is similar to previously described data. A systematical review of studies investigating the frequency of insufficient antiplatelet effects of aspirin described the prevalence to be 24% [24]. Likewise to clopidogrel insufficient effects, factors for HTPR to aspirin are multifactorial. Variable bioavailability, enhanced aspirin degradation, genetic polymorphism of cyclooxygenase, cyclooxygenase-2 mediated thromboxane formation, and drug–drug interactions may be responsible for insufficient aspirin antiplatelet effects [25,26]. Bleeding complications are more frequent than ischemic events in patients undergoing MitraClip procedure. In this study, 27 (37%) patients experienced a bleeding complication (Table 2). The incidence of bleeding complications described in the EVEREST II trial was 13% [2]. However, bleeding complications in the EVERST II trial were defined as transfusion of ≥ 2 U of blood. Minor bleedings and minor vascular complications were not included. Therefore, as in the present study we also considered minor bleedings and minor vascular complications according to the VARC-2 provided standardized definition of clinical complications, it does not surprise, that overall bleeding complications were higher [15]. In our study, major bleedings/vascular complications (transfusion of ≥2 U of blood) accounted for only 8.2% of bleeding complications. Most minor vascular complications were access site related (24 of 27 patients). Ischemic events were rare. There were no ischemic events during hospital course at all. During follow up, one stroke and one acute coronary syndrome occurred (Table 2). Both patients had sufficient aspirin antiplatelet effects; one patient had insufficient clopidogrel antiplatelet effects (Table 4A). However the subgroup is too small to allow reasonable analysis. There were no differences regarding the incidence of HTPR/LTPR to clopidogrel and HTPR to aspirin between patients with- and without bleeding complications (Table 4B). Previously, a correlation between LTPR to clopidogrel and bleeding has been described [6]. However, in our study, the incidence of LTPR was low (six patients). Due to small sample size, it was not surprising, that we were not able to correlate LTPR and bleeding events. Furthermore, the incidence of additional oral anticoagulation also did not differ between patients with- and without bleeding complications. As most of the bleeding complications were access site related and oral anticoagulation was paused periinterventional, this was not surprising at all. At the moment, dual antiplatelet therapy is applied early after MitraClip procedure [2,4]. Existing permanent oral anticoagulation is recommended to be continued as well [5]. In this study, the incidence of HTPR to clopidogrel was very high. Despite that, ischemic complications were rare and bleeding events more frequent. Therefore, one could hypothesize, that single antiplatelet medication with aspirin might be enough. However, alternatively it could be hypothesized that platelet function testing does not add value to predict outcome, as despite being underpowered the association between HTPR and adverse events was not even borderline significant in this study. This would go in line with results of recent trials that failed to improve outcome of CAD patients by tailoring antiplatelet therapy according to results of
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
platelet function assays [27–29]. However, all trials had limitations regarding study design which might partially have led to its negative results [30]. Contradictory, three smaller trials were able to demonstrate, that tailoring antiplatelet therapy is able to improve outcome [31–33]. Moreover, many trials demonstrated an association between HTPR and clinical outcome [6,12–14,34,35]. Therefore, large clinical trials are needed to clarify the situation and investigate the optimal antithrombotic regiment in MitraClip patients. 5. Conclusion In conclusion, the incidence of HTPR to clopidogrel medication is very high. However ischemic events were rare and bleeding events more frequent. Additionally, many patients undergoing MitraClip procedure were on permanent oral anticoagulation because of atrial fibrillation. This finding underlines the need of large scale clinical trials to assess the optimal antiplatelet/anticoagulation regiment in MitraClip patients. These trials should take the high incidence of HTPR to clopidogrel into account and monitor antiplatelet effects accurately. 6. Study limitations We conducted a hypothesis generating pilot study to assess antiplatelet effects of clopidogrel and aspirin in patients undergoing MitraClip procedure. The study was not powered to correlate antiplatelet effects with clinical endpoints. Ethics committee approval The study conformed to the Declaration of Helsinki and was accepted by the University of Düsseldorf Ethics Committee. Source of funding TR is a Heisenberg Professor funded by the German Research Foundation; grant number: DFG RA969/7-2; Grant sponsor: Federal State Government of North Rhine-Westphalia and the European Union (EFRE-Program “Med in.NRW”); grant number: 005-GW01–235A. Disclosures None. Acknowledgments None. References [1] L. Mauri, E. Foster, D.D. Glower, P. Apruzzese, J.M. Massaro, H.C. Herrmann, et al., 4year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation, J. Am. Coll. Cardiol. 62 (4) (2013) 317–328 (Epub 2013/ 05/15). [2] T. Feldman, E. Foster, D.D. Glower, S. Kar, M.J. Rinaldi, P.S. Fail, et al., Percutaneous repair or surgery for mitral regurgitation, N. Engl. J. Med. 364 (15) (2011) 1395–1406 (Epub 2011/04/06). [3] A. Vahanian, O. Alfieri, F. Andreotti, M.J. Antunes, G. Baron-Esquivias, H. Baumgartner, et al., Guidelines on the management of valvular heart disease (version 2012), Eur. Heart J. 33 (19) (2012) 2451–2496 (Epub 2012/08/28). [4] O. Franzen, S. Baldus, V. Rudolph, S. Meyer, M. Knap, D. Koschyk, et al., Acute outcomes of MitraClip therapy for mitral regurgitation in high-surgical-risk patients: emphasis on adverse valve morphology and severe left ventricular dysfunction, Eur. Heart J. 31 (11) (2010) 1373–1381 (Epub 2010/03/12). [5] S. Alsidawi, M. Effat, Peri-procedural management of anti-platelets and anticoagulation in patients undergoing MitraClip procedure, J. Thromb. Thrombolysis 38 (3) (2014) 416–419. [6] U.S. Tantry, L. Bonello, D. Aradi, M.J. Price, Y.H. Jeong, D.J. Angiolillo, et al., Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding, J. Am. Coll. Cardiol. 62 (24) (2013) 2261–2273 (Epub 2013/10/01).
5
[7] P.A. Gurbel, R.C. Becker, K.G. Mann, S.R. Steinhubl, A.D. Michelson, Platelet function monitoring in patients with coronary artery disease, J. Am. Coll. Cardiol. 50 (19) (2007) 1822–1834 (Epub 2007/11/06). [8] T. Rassaf, J. Balzer, T. Zeus, C. Rammos, S. Shayganfar, S.V. Hall, et al., Safety and efficacy of deep sedation as compared to general anaesthesia in percutaneous mitral valve repair using the MitraClip(R) systemOfficial Journal of the Society for Cardiac Angiography & Interventions Catheter. Cardiovasc. Interv. 84 (4) (2014) E38–E42 (Epub 2014/06/10). [9] T. Feldman, S. Kar, M. Rinaldi, P. Fail, J. Hermiller, R. Smalling, et al., Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort, J. Am. Coll. Cardiol. 54 (8) (2009) 686–694 (Epub 2009/08/15). [10] T. Garabedian, S. Alam, High residual platelet reactivity on clopidogrel: its significance and therapeutic challenges overcoming clopidogrel resistance, Cardiovasc. Diagn. Ther. 3 (1) (2013) 23–37 (Epub 2013/11/28). [11] K. Schror, K. Huber, T. Hohlfeld, Functional testing methods for the antiplatelet effects of aspirin, Biomark. Med. 5 (1) (2011) 31–42 (Epub 2011/02/16). [12] P.A. Gum, K. Kottke-Marchant, P.A. Welsh, J. White, E.J. Topol, A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease, J. Am. Coll. Cardiol. 41 (6) (2003) 961–965 (Epub 2003/03/ 26). [13] N.J. Breet, J.W. van Werkum, H.J. Bouman, J.C. Kelder, J.M. Ten Berg, C.M. Hackeng, High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events, J. Thromb. Haemost. 8 (10) (2010) 2140–2148 (Epub 2010/08/21). [14] G. Krasopoulos, S.J. Brister, W.S. Beattie, M.R. Buchanan, Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis, BMJ 336 (7637) (2008) 195–198 (Epub 2008/01/19). [15] A.P. Kappetein, S.J. Head, P. Genereux, N. Piazza, N.M. van Mieghem, E.H. Blackstone, et al., Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document, Eur. Heart J. 33 (19) (2012) 2403–2418 (Epub 2012/10/03). [16] R. Pisters, D.A. Lane, R. Nieuwlaat, C.B. de Vos, H.J. Crijns, G.Y. Lip, A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey, Chest 138 (5) (2010) 1093–1100 (Epub 2010/03/20). [17] N. Mallouk, C. Labruyere, J.L. Reny, C. Chapelle, M. Piot, P. Fontana, et al., Prevalence of poor biological response to clopidogrel: a systematic review, Thromb. Haemost. 107 (3) (2012) 494–506 (Epub 2012/01/26). [18] T. Cuisset, J. Quilici, P.E. Morange, J.L. Bonnet, M.C. Alessi, Predictors of long-term high on-treatment platelet reactivity in clopidogrel-treated patients undergoing coronary stenting for acute coronary syndrome, Int. J. Cardiol. 168 (2) (2013) 1565–1566 (Epub 2013/01/22). [19] A. Darlington, A. Tello-Montoliu, F. Rollini, M. Ueno, J.L. Ferreiro, R. Patel, et al., Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease, Thromb. Haemost. 111 (2) (2014) 258–265 (Epub 2013/10/25). [20] O. Ait-Mokhtar, L. Bonello, S. Benamara, F. Paganelli, High on treatment platelet reactivity, Heart Lung Circ. 21 (1) (2012) 12–21 (Epub 2011/10/18). [21] J. Silvain, G. Cayla, J.S. Hulot, J. Finzi, M. Kerneis, S.A. O'Connor, et al., High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIORPLATELET study, Eur. Heart J. 33 (10) (2012) 1241–1249 (Epub 2011/11/10). [22] J. Silvain, A. Bellemain-Appaix, O. Barthelemy, F. Beygui, J.P. Collet, G. Montalescot, Optimal use of thienopyridines in non-ST-elevation acute coronary syndrome following CURRENT-OASIS 7, Circ. Cardiovasc. Interv. 4 (1) (2011) 95–103 (Epub 2011/02/18). [23] N.L. Cruden, K. Morch, D.R. Wong, W.P. Klinke, J. Ofiesh, J.D. Hilton, Clopidogrel loading dose and bleeding outcomes in patients undergoing urgent coronary artery bypass grafting, Am. Heart J. 161 (2) (2011) 404–410 (Epub 2011/02/15). [24] M.M. Hovens, J.D. Snoep, J.C. Eikenboom, J.G. van der Bom, B.J. Mertens, M.V. Huisman, Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review, Am. Heart J. 153 (2) (2007) 175–181 (Epub 2007/01/24). [25] T. Hohlfeld, A. Saxena, K. Schror, High on treatment platelet reactivity against aspirin by non-steroidal anti-inflammatory drugs — pharmacological mechanisms and clinical relevance, Thromb. Haemost. 109 (5) (2013) 825–833 (Epub 2012/12/15). [26] A. Polzin, T. Zeus, K. Schror, M. Kelm, T. Hohlfeld, Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease, J. Am. Coll. Cardiol. 62 (18) (2013) 1725–1726 (Epub 2011/03/17). [27] M.J. Price, P.B. Berger, P.S. Teirstein, J.F. Tanguay, D.J. Angiolillo, D. Spriggs, et al., Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial, JAMA 305 (11) (2011) 1097–1105 (Epub 2011/03/17). [28] G. Montalescot, G. Range, J. Silvain, J.L. Bonnet, Z. Boueri, O. Barthelemy, et al., High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: a landmark analysis of the ARCTIC study, Circulation 129 (21) (2014) 2136–2143 (Epub 2014/04/11). [29] D. Trenk, G.W. Stone, M. Gawaz, A. Kastrati, D.J. Angiolillo, U. Muller, et al., A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study, J. Am. Coll. Cardiol. 59 (24) (2012) 2159–2164 (Epub 2012/04/24). [30] J.M. Siller-Matula, B. Jilma, Why have studies of tailored anti-platelet therapy failed so far? Thromb. Haemost. 110 (4) (2013) 628–631 (Epub 2013/07/26).
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015
6
A. Polzin et al. / Vascular Pharmacology xxx (2015) xxx–xxx
[31] L. Bonello, L. Camoin-Jau, S. Armero, O. Com, S. Arques, C. Burignat-Bonello, et al., Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis, Am. J. Cardiol. 103 (1) (2009) 5–10 (Epub 2008/12/23). [32] L. Bonello, L. Camoin-Jau, S. Arques, C. Boyer, D. Panagides, O. Wittenberg, et al., Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study, J. Am. Coll. Cardiol. 51 (14) (2008) 1404–1411 (Epub 2008/04/05). [33] T. Cuisset, C. Frere, J. Quilici, P.E. Morange, J.P. Mouret, L. Bali, et al., Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders:
a prospective, randomized study, J. Am. Coll. Cardiol. Intv. 1 (6) (2008) 649–653 (Epub 2009/05/26). [34] N.J. Breet, J.W. van Werkum, H.J. Bouman, J.C. Kelder, H.J. Ruven, E.T. Bal, et al., Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation, JAMA 303 (8) (2010) 754–762 (Epub 2010/02/25). [35] K. Mayer, I. Bernlochner, S. Braun, S. Schulz, M. Orban, T. Morath, et al., Aspirin treatment and outcomes after percutaneous coronary intervention: results of the ISARASPI registry, J. Am. Coll. Cardiol. 64 (9) (2014) 863–871 (Epub 2014/08/30).
Please cite this article as: A. Polzin, et al., Platelet reactivity in MitraClip patients, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.07.015