J Nephrol

DOI 10.1007/s40620-016-0367-5

REVIEW

Antiplatelet agents in hemodialysis

Massimiliano Migliori1 · Vincenzo Cantaluppi2 · Alessia Scatena1 ·
Vincenzo Panichi1

Received: 5 August 2016 / Accepted: 21 November 2016

© Italian Society of Nephrology 2016

Abstract Patients afected by cardiovascular disease new AA drugs in hemodialytic patients. In conclusion,
(CVD) are treated with antiplatelet agents (AA) and/or since CRF patients are one of the groups at highest risk for
anticoagulant drugs, which are fundamental in the manage- atherosclerotic events, it could be reasonable to use aspirin
ment of stroke, coronary atherosclerotic disease, peripheral in HD patients. However, the bleeding risk in HD patients
vascular disease and atrial ibrillation. CVD is the most needs to be strongly evaluated, especially before starting
important cause of death in chronic renal failure (CRF). dual AA treatment.
Death rates from myocardial infarction (MI) and from all
other cardiac causes exceed those for the general popula- Keywords Antiplatelet drugs · Chronic renal failure ·
tion. Incidence of MI in CRF is triple that in the general Hemodialysis · Cardiovascular disease · Aspirin
population. Moreover, mortality is seven- to eight-fold
higher in patients requiring chronic hemodialysis compared Abbreviations
to the general population, and approximately 40% of deaths AA Antiplatelet agents
in this population are attributable to coronary artery disease AF Atrial ibrillation
(CAD). For these reasons, AA are widely used in patients AR Aspirin resistance
afected by CRF. Current data do not support a protective BMS Bare metal stent
efect of antiplatelet administration in hemodialytic patients CABG Coronary artery bypass grafting
as primary prevention of cardiovascular mortality. Diferent CAD Coronary atherosclerotic disease
results have been obtained concerning secondary preven- cAMP Cyclic adenosine monophosphate
tion of CVD. The Cooperative Cardiovascular Project dem- cGMP Cyclic guanosine monophosphate
onstrated that dialysis patients treated with aspirin follow- CYP Cytochrome P450 monoxygenase system
ing MI had a 43% lower mortality. Another study reported CKD Chronic kidney disease
that the use of aspirin and beta-blockers following MI was COX Cyclooxygenase
associated with lower mortality in CRF patients. However, CVD Cardiovascular disease
aspirin plus clopidogrel seems to increase the hemorrhagic DES Drug eluting stent
risk without a signiicant reduction in cardiovascular mor- ESRD End stage renal disease
tality and there are insuicient data to support the use of GP Glycoprotein
HD Hemodialysis
HPR High platelet reactivity
* Massimiliano Migliori MI Myocardial infarction
maxmigliori@yahoo.it OAC Oral anticoagulant
1 PAF Platelet aggregating factor
Nephrology and Dialysis, Azienda USL Nord Ovest Toscana,
Versilia Hospital, Versilia, Italy PAR-1 Protease-activated receptor 1
2 PCI Percutaneous coronary intervention
Nephrology and Kidney Transplant Unit, Department
of Translational Medicine, University of Eastern Piedmont, PLT Platelets
Novara, Italy PTCA Percutaneous transluminal coronary angioplasty

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TxA2 Thromboxane A2 attributable to CAD [10]. For these reasons AA are widely
5HT 5 hydroxytryptamine used in patients afected by CKD. The aim of this review is
5AMP 5 adenosine monophosphate to discuss role of AA in patients undergoing chronic HD.

Introduction Platelet pathophysiology and anti-platelet agents

In their clinical practice, nephrologists encounter patients It is well known, that platelets (PLT) are fundamental com-
afected by cardiovascular disease (CVD) on therapy with ponents of hemostasis and they actively participate in the
antiplatelet agents (AA) and/or anticoagulant drugs, cor- atherogenic process by virtue of their capacity to adhere to
nerstones of the primary and secondary management of injured blood vessels and to accumulate at sites of injury
atherosclerotic thrombotic disease [1] such as stroke [2], [11]. PLT are involved in the repairing of issured athero-
coronary artery disease (CAD) [3], peripheral vascular dis- sclerotic plaque. However, the uncontrolled progression of
ease [4] and atrial ibrillation (AF) [5]. A meta-analysis of this process may lead to thrombus formation, and vascular
the Antithrombotic Trialists’ Collaboration demonstrated occlusion with transient or permanent ischemia or necrosis.
that AA therapy reduced the risk of non-fatal myocardial This aberrant PLT activation occurs in many pathological
infarction (MI), non-fatal stroke, or vascular death by 25% conditions such as MI, ischemia, and stroke, and for this
also among other patients with coronary or peripheral arte- reason AA are a cornerstone of the treatment for CVD.
rial disease and those at high risk of embolism. Overall,
mortality was also signiicantly reduced in these high-risk Antiplatelet agents
patients, and, compared with the beneits, the absolute risk
of fatal and major nonfatal bleeds was small [5]. The risk Currently available AA and investigational agents are clas-
of a recurrent ischemic event is three-fold higher in patients siied on the basis of their ability to interfere with some of
discontinuing aspirin especially in those on secondary pre- the steps leading to PLT aggregation, as reported in Table 1
vention for CAD and those undergoing coronary artery and Fig. 1.
bypass grafting (CABG) or treated with a drug eluting stent Aspirin inhibits cyclooxygenase (COX) by acetylating
(DES) [6]. Moreover, some patients require anticoagulation a serine residue in the catalytic site for the enzyme. This
for the prevention of strokes and systemic embolisms, as prevents arachidonic acid from gaining access to the cata-
well as antiplatelet therapy for the prevention of recurrent lytic site of the enzyme [12]. The major adverse efect is an
MI and stent thrombosis that can be complicated by death increased risk of bleeding complications, albeit with a very
or a large MI [7]. favorable risk–beneit ratio [13]. However, from 2 to 57%
In patients with AF, the incidence of CAD is 34%, of treated patients have an inadequate response to aspirin at
with 21% of patients subsequently requiring percutaneous doses of 300 mg daily [14]. These patients are discovered
transluminal coronary angioplasty (PTCA) or CABG. On by using an in vitro test of PLT function (with assay limits
the contrary, patients presenting with acute coronary syn- deined for the test by the investigator) and are described
dromes (ACS) develop AF in 6–21% of cases, requiring as having “high platelet reactivity (HPR)” or “biochemical
anticoagulation too. In patients undergoing elective PTCA resistance” [15]. HPR is an ex vivo diagnosis based on test-
with a bare metal stent (BMS) or DES implantation, triple ing and should be considered as a primary event. Clinical
therapy with aspirin, clopidogrel and an oral anticoagulant thrombosis is a very late sign of HPR if it is present, but
(OAC) was prescribed for 4 weeks and 3–6 months, respec- it is not a deinitive proof that HPR is the cause of throm-
tively, followed by dual therapy (one AA plus OAC) for up bosis. Diferences in thrombotic outcomes for patients
to 1 year. Moreover, in ACS patients, triple therapy was whose AA dosing was based on ex vivo PLT function test
recommended for 4 weeks or 3–6 months (or longer), fol- results have been demonstrated [16]. Possible mechanisms
lowed by dual therapy for up to 1 year [3]. for HPR include: inlammatory response, genetic polymor-
CVD is the most important cause of death in chronic phisms of the PLT glycoprotein receptor [17] and COX-1
kidney disease (CKD). As previously reported by Foley and COX-2 alleles [18], generation of aspirin-sensitive
[8], death rates from MI and from all other cardiac causes COX [19], and increased PLT turnover [20]. Unfortunately,
exceed those for the general population. Incidence of MI some patients with an inadequate response to aspirin may
in chronic renal failure (CRF) is triple that for the general also have an inadequate response to clopidogrel (i.e. dual
population [9]. Moreover, the mortality rate is seven- to “resistance”), which may be particularly prevalent among
eight-fold greater in patients requiring chronic hemo- women and diabetics [21].
dialysis (HD) compared with the general population, Ticlopidine is a irst-generation oral thienopyridine that
and approximately 40% of deaths in this population are requires cytochrome P450 1A metabolism prior to exerting

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Table 1 Classiication of antiplatelet drugs

COX-1 inhibitors Reversible Indobufen, NSAID

Irreversible Aspirin
P2Y12 receptor inhibitors Reversible Cyclopentyltriazolopyrimidine Ticagrelor
ADP analog Cangrelor
Sulfonylurea Elinogrel (i.v.)
Irreversible Thienopyridine Ticlopidine,
Clopidogrel,
Prasugrel
Phosphodiesterase inhibitors Reversible Pyrimidopyrimidine Dipyridamole
Phosphodiesterase III inhibitor Cilostazol
Glycoprotein (GP) IIb/IIIa blockers Non-competitive inhibitor humanized chimeric Fab fragment of Abciximab
monoclonal mouse antibody
Competitive inhibitor Cyclic heptapeptide Eptiibatide
Nonpeptide antagonist Tiroiban
Protease-activated receptor-1 (PAR-1) Competitive inhibitor of thrombin induced platelet aggregation Vorapaxar
antagonists Atopaxar

Fig. 1 Agonists to platelet activation and antiplatelet drugs (modiied by Hall et al. [22])

its irreversible antagonistic efects on PLT reactivity via administration, the drug bioavailability is approximately
the P2Y12 receptor [23]. Early experimental observations 50%; moreover, 85% of the adsorbed drug is hydrolyzed
showed that the agonist-induced PLT aggregation was to an inactive metabolite [27]. The active metabolite irre-
intermittently inhibited by ticlopidine. Maximal inhibition versibly inhibits the P2Y12 receptor. Recovery of PLT
of PLT aggregation is observed 3–5 days post administra- function after drug withdrawal occurs over 7–8 days as
tion of ticlopidine due to pro-drug metabolism [24]. Ticlo- a function of PLT turnover. The ‘Clopidogrel in Unsta-
pidine is more efective than aspirin alone [25], and minor ble angina to prevent Recurrent Events’ (CURE) trial has
bleeding and hemorrhagic events are observed in <1% shown the clinical beneit of the dual clopidogrel-aspirin
of treated subjects. The main secondary adverse events therapy compared to aspirin alone—the dual therapy sig-
include diarrhea, skin rash, and neutropenia [26]. The dos- niicantly reduced mortality and nonfatal MI or stroke
age of ticlopidine may need to be reduced or discontinued in patients with unstable angina, although it was associ-
in patients with moderate to severe renal failure especially ated with an increase in bleeding compared to placebo
if hematologic side efects occur. [28]. The ‘Clopidogrel versus Aspirin in Patients at Risk
Clopidogrel is a second generation oral thienopyri- of Ischemic Events’ (CAPRIE) trial, which evaluated
dine, also requiring CYP2C19 metabolism. After oral the eicacy of clopidogrel compared to aspirin, showed

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clopidogrel treatment resulted in a reduction of pri- Cilostazol is a type III phosphodiesterase (PDE) oral
mary endpoints [29]. Evidence of poor metabolizers for reversible inhibitor. It inhibits adenosine uptake enhanc-
clopidogrel has helped to explain the reduced function ing its interstitial concentration [45]. Cilostazol reduces
in patients with an altered CYP2C19 allele [30]. Poor the incidence of repeated revascularization after percuta-
metabolizers of clopidogrel have diminished PLT inhibi- neous coronary interventions (PCI) and the risk of reste-
tion resulting in a higher rate of adverse cardiovascular nosis. However, it is not superior in reducing the primary
events than in noncarriers [31]. composite endpoints of adverse cardiovascular events after
HPR also occurs with clopidogrel administration [32]. DES implantation [46]. Despite the functional implica-
Many of the same factors leading to aspirin HPR apply tions of adjunctive treatment with cilostazol compared with
also to clopidogrel HPR, but intrinsic factors that afect the standard aspirin and clopidogrel treatment, as shown in
interaction of active metabolite with its receptors (such as the Optimizing anti-Platelet Therapy In diabetes MellitUS
genetic alterations in the CYP2C19 gene, P2Y12 recep- (OPTIMUS)-2 study, the accompanying side efects (head-
tor polymorphisms, or alterations in intracellular signal- aches, gastrointestinal symptoms, and skin rash) often lead
ing mechanisms) may also be involved [33–35]. Moreover, to the discontinuation of the drug [47].
some patients demonstrated HPR in response to treatment Dipyridamole is a pyridopyrimidine derivative that
with both aspirin and clopidogrel [36]. These patients have enhances adenosine concentration by blocking its uptake
a very high risk of DES thrombosis or death [37]. Although and inhibiting cyclic nucleotide phosphodiesterase and
dual AA HPR may occur, HPR to one class of AA does this results in antiplatelet and vasodilator activity [48].
not confer HPR to other classes of AA. Sometimes, non- Dual treatment of dipyridamole and aspirin reduced risk
responders to a 300-mg initial loading dose of clopidogrel of stroke or death by 37% compared with aspirin alone,
can be converted to responders by increasing either the as reported in the ‘European Stroke Prevention Study’
loading dose [38] or the maintenance dose [39], or both (ESPS)-2 and ‘European/Australasian Stroke Prevention
[40]. in Reversible Ischemia’ (ESPRIT) trials [49, 50]. Based
Prasugrel is a pro-drug that irreversibly inhibits P2Y12 on these trials, dipyridamole has been FDA-approved for
receptor. It is administered orally and requires active trans- stroke prevention [50].
formation via the cytochrome P450 monoxygenase system
(CYP450). It is more efective than clopidogrel after a sin-
gle dose in healthy subjects [41]. A loading dose of prasu- Platelet function, coagulation system
grel (60 mg) resulted in a ~10-fold higher active metabolite and hemodialysis
generation with respect to clopidogrel 300 mg, and this is
the pharmacokinetic basis for its more eicient and less Platelet abnormalities
variable inhibition of PLT function both in healthy sub-
jects [42] and in patients [43]. Its major adverse efect is In HD patients, PLT abnormalities may induce either a
bleeding, especially in patients with a history of stroke or bleeding tendency or an increase in thrombotic complica-
transient ischemic attack (TIA), suggesting that prasugrel tions. Previous studies reported that a decreased membrane
should be avoided in patients with known cerebrovascular expression or an abnormal activation of platelet receptors
disease, or that its maintenance dose should be reduced. [51, 52], or an increase in platelet receptor number may be
Ticagrelor is an oral cyclopentyl-triazolo-pyrimidine related to frequent access obstruction [53]. However, PLT
pro-drug and it is a direct and reversible inhibitor of the are activated by adherence to the extracorporeal circuit high
P2Y12 receptor. The ‘Platelet Inhibition and Patient Out- shear stress and turbulence in the vascular access [54, 55]
comes’ (PLATO) trial demonstrated that in patients who and artiicial surface of the polytetraluoroethylene (PTFE)
had an ACS with or without ST-segment elevation, tica- graft [56, 57]. Finally, also native arteriovenous istula may
grelor, as opposed to clopidogrel, signiicantly reduced the activate PLT by a mechanism involving ibrinogen, which
rate of death from vascular causes, myocardial infarction, is increased in HD [58]. Factors released by activated PLT
or stroke, without an increase in the rate of overall major may also create a pro-thrombotic microenvironment.
bleeding but with an increase in the rate of non-procedure-
related bleeding. Moreover, in ACS patients initially medi- Plasma factor abnormalities
cally treated, ticagrelor achieved an important reduction
in ischemic events and mortality compared to clopidogrel, Sacripanti et al. [59] previously demonstrated that CRF is a
without increasing major bleeding. Moreover, the reduction prothrombotic state and HD patients show a higher degree
of ischemic events and mortality by ticagrelor over clopi- of hypercoagulation. Moreover, signiicantly higher levels
dogrel was consistent in ACS patients with non-ST eleva- of thrombin-antithrombin III complex, ibrinopeptide A,
tion revascularization [44]. D-dimer, von Willebrand factor, tissue-type plasminogen

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activator, beta-thromboglobulin, platelet factor 4 and sero- of bleeding with low-dose aspirin, it also failed to demon-
tonin have been demonstrated in HD patients. Furthermore, strate any beneit in terms of cardiovascular morbidity and
HD patients have higher levels of ibrinogen [59, 60] and mortality. Other studies failed to demonstrated a diference
antithrombin III levels and antithrombin III activity may in major bleeding in HD patients treated or not with AA
be reduced [61, 62]. Other studies have reported elevated [68].
lupus anticoagulant antibody titers in up to one-third of HD
patients [63]. Secondary prevention

Diferent results were obtained in secondary prevention of

Antiplatelets and hemodialysis CVD. In a multivariate analysis of the Cooperative Cardio-
vascular Project, dialysis patients treated with aspirin fol-
The beneits and risks of AA remain unclear in HD lowing MI had a 43% lower mortality during the follow-
patients: as reported in the ‘Dialysis Outcomes and Practice ing 30 days [69]. Another observational retrospective study
Patterns Study’ (DOPPS), the use of AA in HD varied from reported that the use of aspirin and beta-blockers following
3 to 25% among the countries investigated [64]. MI was associated with lower mortality in CKD patients
[70]. Thus, there are reasonable data to support the use of
Primary prevention aspirin following MI.

There are no data on use of aspirin in primary prevention Myocardial infarction

of CVD in dialysis patients. In an observational study of
3374 incident dialysis patients with and without CVD in Myocardial revascularization has become a common thera-
the US Renal Data System (USRDS) Dialysis Morbidity peutic option in HD patients, and coronary stenting in these
Mortality Wave II Study, patients on aspirin had a 2.9-fold patients has increased by 50% over the past decade. In
higher hazard of ACS in unadjusted analysis [65]. How- these patients the dual antiplatelet treatment is the corner-
ever, this result was not signiicant at multivariate analysis. stone treatment, and the recommendations for the general
The authors suggested that this could be explained by the population have been adapted to the HD setting because
evidence that use of aspirin was more common in patients randomized controlled trials (RCTs) are lacking. A previ-
with pre-existing CVD than in those without (32.5% vs. ous study reported a lower probability of bleeding in HD
11.4%; p < 0.05). Moreover, a high prevalence of aspirin patients with an optimized treatment of anemia [71] sup-
resistance has been reported in HD patients [66]. Ethier porting an improved safety when antiplatelet therapy is part
et al. [67] reported that in 28,320 randomly selected HD of a global therapeutic strategy.
patients from DOPPS I and II, aspirin prescription at base- The ESC guidelines [72] reported two diferent clinical
line was associated with a decreased risk of stroke in all presentations of ACS:
patients [relative risk (RR) 0.82; p < 0.01], an increased
risk of myocardial infarction (RR 1.21; p = 0.01) and car- 1. Patients with acute chest pain and persistent (>20 min)
diac events (RR 1.08; p < 0.01) in all patients, with similar ST-segment elevation (STE-ACS), which generally
results for patients with CAD. They reported no increase in relects an acute total coronary occlusion. Most of
gastrointestinal bleeding. these patients will ultimately develop an ST-elevation
The efect of AA among HD patients after place- MI (STEMI). The therapeutic objective is to achieve
ment of a dialysis shunt or istula was investigated by the rapid, complete, and sustained reperfusion by primary
Antithrombotic Trialists’ Collaboration [5]. Overall, among angioplasty or ibrinolytic therapy.
2,632 patients from 14 trials during a follow-up of 12–18 2. Patients with acute chest pain but without persistent
months, antiplatelet therapy produced a 41% proportional ST-segment elevation. These patients have rather per-
reduction in serious vascular events (non-fatal MI, non- sistent or transient ST-segment depression or T-wave
fatal stroke, or vascular death) compared with a 22% odds inversion, lat T waves, pseudo-normalization of T
reduction seen in the overall study population. However, waves, or no ECG changes at presentation. The ini-
this result was based on only 99 vascular events among tial strategy is to alleviate ischemia and symptoms, to
such patients and the diference was not statistically sig- monitor the patient with serial ECGs, and to repeat
niicant. Extracranial major bleeds were 2.0% in antiplate- measurements of markers of myocardial necrosis. At
let treated patients versus 2.3% in the adjusted controls. presentation, the working diagnosis of non-ST-eleva-
DOPPS was an observational study on the safety and sec- tion ACS (NSTE-ACS), based on the measurement of
ondary prevention eicacy of aspirin in 28,320 HD patients troponins, will be further qualiied as non-ST-elevation
worldwide [67]. Although it did not show an increased risk MI (NSTEMI) or unstable angina.

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As extensively reviewed by Summaria et al. [73], obser- healthy subjects with normal renal function has been
vational studies suggest that patients with CKD undergo- completed, but no results are posted (ClinicalTrials.gov
ing revascularization have better short- and long-term sur- Identiier: NCT02022748).
vival than those receiving medical therapy alone [74–76], A meta-analysis by Palmer et al. [68] on 13 stud-
especially during ACS. However, HD patients, having an ies reported no diferences in all-cause mortality among
increased risk of periprocedural ischemic and bleeding 4,363 HD patients treated or not with AA [RR 0.82 (95%
complications, are excluded from most RCTs on revascu- conidence interval (CI) 0.63–1.06); p = 0.30]. Moreo-
larization; hence, current treatment strategies are based on ver, in the same study, antiplatelet therapy was accom-
retrospective analyses of RCTs and data from registries. panied by a non-signiicant reduced risk of fatal or non-
The results from the USRDS (21,981 patients) suggest fatal MI. Fourtounas and Panagiotou [81] suggested that
that CABG should be preferred to PCI in end-stage renal this discrepancy may be due to the fact that the studies
disease (ESRD) only for multivessel coronary disease and included in the analysis, were referring to ACS treated by
in appropriately selected non ACS patients [77]. The ESC PCIs with non DES, which have been associated to worse
guidelines on myocardial revascularization for ESRD indi- outcomes in high-risk populations. Moreover, the use of
cated that the most appropriate revascularization strategy clopidogrel in dialysis patients may rely on the residual
must account for the general condition and life expectancy, PLT reactivity (aggregability) that persists at a higher
the least invasive approach being more appropriate in the level than that required for an optimal anti-ischemic
most fragile and compromised patients, suggesting PCI as efect (“high on clopidogrel platelet reactivity”). This is
a more suitable coronary revascularization strategy. When highly prevalent in HD patients even with increased dos-
PCI is indicated, a newer generation DES [78] should be ing of clopidogrel (150 mg daily) [82].
preferred over BMS, because of its lower risk of restenosis Prasugrel [83] or ticagrerol [84] have been associated
and improved safety concerns (stent thrombosis) [79, 80]. with better PLT inhibition in HD patients but these stud-
Management of NSTEMI has less consensus than that ies included a small number of patients for a limited time
for STEMI in HD patients. The ESC guidelines recom- period. Of interest, a level of laboratorial “resistance” to
mend for patients who did not receive reperfusion therapy the treatment was observed in 19% of these cases even
ASA 150–500 mg loading dose, then 75–100 mg daily with prasugrel inhibition, which has been considered
indeinitely, plus clopidogrel 75 mg daily for at least 1 as more potent compared to clopidogrel [83]. The inad-
month and up to 12 months. Aspirin should be admin- equate PLT inhibition achieved by these agents may be
istered in low-dose regimens (<100 mg) life-long, and due to various reasons such as CYP polymorphisms,
clopidogrel remains the only choice in the case of PCI in altered drug metabolism from uremia or the rather con-
a stable clinical setting and, regardless of the clinical set- tinuous production of “fresh” PLT with active receptors,
ting, in patients requiring P2Y12-inhibiting therapy with mainly due to the exogenous erythropoietin administra-
a basal high risk of bleeding (including patients taking tion, which acts as a promoter of PLT production from
oral anticoagulant therapy). Prasugrel should be consid- the bone marrow via iron deiciency [85].
ered only in patients with ACS undergoing PCI with an On the other hand, HD patients present higher bleed-
individual ischemic risk and/or thrombotic burden higher ing rates compared to the general population, especially
than the bleeding risk (i.e. diabetic, STEMI, stent throm- with the combination of these agents [86]. Although
bosis in clopidogrel-treated patients). It should be used the exact bleeding rates in dialysis patients under anti-
with caution in patients with low weight and the elderly platelet therapy remains poorly deined, Kaufman et al.
(>75 years) possibly at a 5 mg reduced dose. It is con- reported a rate of approximately 0.5 episodes/patient-year
traindicated in patients with a prior TIA/stroke or pre- of follow-up monitoring in the placebo arm of their ran-
vious intracranial hemorrhage. Ticagrelor can be used domized study for the prevention of HD synthetic graft
across the spectrum of ACS until CKD-stage 4, but its thrombosis and a signiicantly increased rate of bleed-
use should be carefully considered in patients with poor ing (almost double) in the aspirin plus clopidogrel arm
compliance given its twice-daily administration. Ticagre- [87]. The metaanalysis by Palmer et al. [68] conirmed
lor is contraindicated in patients with prior hemorrhagic these adverse efects, reporting an increased risk of major
stroke and severe hepatic impairment and should be cau- (33%) or minor (49%) bleeding in CKD patients under
tiously used in patients treated with potent inhibitors or antiplatelet therapy for various reasons. In addition, many
inducers of CYP3A, due to potential drug interactions. transplant centers are reluctant to list CKD patients under
Moreover, in the PLATO study, patients requiring dial- clopidogrel therapy for renal transplantation, due to the
ysis were excluded. Today, a phase I, open-label study increased risk of perioperative bleeding, which may be
comparing the pharmacokinetics, pharmacodynamics, life-threatening and can be treated only by massive trans-
safety and tolerability of ticagrelor in HD patients versus fusions of fresh PLT.

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Peripheral artery disease patients with ischemic stroke plus CKD. As CKD patients
have distinct characteristics including high bleeding com-
Patients with CKD also seem to be at increased risk for plications and poor response to antiplatelet agents, select-
developing claudication and for requiring surgical interven- ing and adjusting of platelet aggregation inhibitors must be
tion for lower extremity peripheral artery disease (PAD). individualized. In addition, it should be noted that aspirin
Furthermore, even moderate CKD seems to be a risk fac- may aggravate renal dysfunction. PDE inhibitors restore
tor for postoperative death and complications after both endothelial dysfunction and may serve as a target for pre-
lower extremity amputation and revascularization proce- venting stroke in CKD patients. Aside from antiplatelet
dures. Conversely, even asymptomatic PAD seems to be a therapy, other treatments including lipid control and blood
risk factor for death among dialysis patients. In the general pressure lowering are mandatory. Further studies are war-
population, statins, antiplatelet agents (particularly clopi- ranted for optimal treatment for stroke prevention in CKD
dogrel), antihypertensive agents, and angiotensin-convert- patients [90].
ing enzyme (ACE) inhibitors all have a proven beneit in
reducing cardiovascular events in patients with PAD and Vascular access
in some instances may also reduce PAD events. Available
evidence suggests that patients with CKD also experience Studies of AA used for access preservation in HD patients
cardiovascular risk reduction with statin and ACE-inhibitor have had mixed results. Hiremath et al. [91] performed a
therapy, but these therapies have not been shown to reduce systematic review to evaluate the bleeding risk associated
PAD events speciically in patients with CKD. Further with long-term antiplatelet use and the eicacy of AA in
studies are needed to identify interventions that can specii- reducing access thrombosis. A total of 40,676 patients with
cally reduce the incidence of PAD complications in patients ESRD were included from 16 studies, with 9186 patients
with CKD [88]. being exposed to an AA. The authors reported that the
use of a single AA did not appear to increase the risk of
Atrial ibrillation bleeding, with the possible exception of aspirin concern-
ing which the study results were mixed. However, AA used
The optimal management of thromboprophylaxis in in combination does appear to signiicantly increase the
patients with CKD and AF is complex given that in patients risk of bleeding: an RCT of aspirin plus clopidrogel ver-
with CKD many physiologic mechanisms are altered, lead- sus placebo to prevent arteriovenous (AV) graft thrombosis
ing to substantial changes in hemostasis and, thus, this was terminated early because of gastrointestinal bleeding.
group of patients is characterized by an increased risk of Moreover, the current literature review does not support the
thrombotic and hemorrhagic complications. Guidelines use of AA for maintenance of the HD vascular access. The
on the treatment of patients with AF do not include rec- authors concluded that an individualized risk assessment
ommendations on how to manage patients with advanced should be considered before initiating AA in HD patients.
CKD, due to the lack of large RCTs assessing the eicacy In the RISCAVID study [92] ticlopidine administration
and beneits of drugs in these patients. Patients with CKD was shown to reduce vascular graft thrombosis in a popula-
and permanent, persistent, and paroxysmal AF ought to be tion of prevalent chronic HD patients (unpublished data).
treated as a group with a high risk of bleeding and ischemic However, a recent meta-analysis and review of the litera-
stroke. In the case of patients with no or only one moderate ture by Palmer et al. [93] (21 eligible trials, 4826 partici-
risk factor, it seems that anticoagulation with antiplatelet pants) reported that antiplatelet treatment reduced istula
drugs can be considered as an efective therapy, while in failure (thrombosis or loss of patency) by one-half [6 trials,
patients with ≥2 risk factors an oral anticoagulation ther- 1222 participants; RR 0.49 (95% CI 0.30–0.81)] but had
apy may be used [89]. uncertain efects on graft patency and attaining of a istula
or graft function suitable for dialysis. Overall, antiplatelet
Stroke treatment had uncertain efects on major bleeding. Similar
results have been reported by Coleman et al. [94].
The incidence and prevalence of CKD increases with age, More recently, the prophylactic efect of diferent anti-
and patients with CKD are a population at very high risk coagulant agents, preparations, doses and administration
for developing stroke. CKD may increase the risk for inci- on the incidence of central venous hemodialysis catheter-
dent stroke independent of conventional stroke risk factors, related malfunction and sepsis in patients with ESRD has
and it has been linked with markers of cerebral small artery been reviewed by Wang et al. [95]. No signiicant efect on
disease including white matter lesions, lacunar infarc- all-cause mortality was observed for alternative anticoagu-
tions, and cerebral microbleeds. However, there have been lant locking solutions [RR 0.88 (0.54–1.43)] or systemic
no speciic recommendations for antiplatelet therapy in agents [RR 0.78 (0.37–1.65)], while data were not reported

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in studies with low or no dose heparin. Bleeding events Compliance with ethical standards
were only reported in eight studies, including only 2/5 stud-
ies of systemic warfarin, with no clear efect demonstrated Conlict of interest The authors declare they have no conlict of in-
[RR 1.43 (0.86–2.39)]. In conclusion, the current literature terest.
review does not support the use of AA for maintenance of Ethical approval This article does not contain any studies with
the HD vascular access. human participants performed by any of the authors.

Informed consent For this type of study formal consent is not

Conclusions required.

This review suggests that the eicacy of AA in HD patients

is not well established as it is in general population. The
RISCAVID study [92] reported that in prevalent HD References
patients total mortality was 12.9%/year whereas cardiovas-
1. Jennings LK (2009) Role of platelets in atherothrombosis. Am J
cular mortality was 5.9%/year. Moreover, in these patients
Cardiol 103:4A–10A
cardiovascular mortality was partially due to thrombotic 2. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P (2008)
events. ANZDATA 2009 reported that about half of car- Antithrombotic and thrombolytic therapy for ischemic stroke:
diovascular deaths in dialysis are caused by cardiac arrest American College of Chest Physicians Evidence- Based Clinical
Practice Guidelines [8th Edition]. Chest 133:630S–639S
and heart failure for which the predominant pathogenetic
3. Harrington RA, Becker RC, Cannon CP, Gutterman D, Lin-
mechanisms include hypertension, volume expansion, vas- cof AM, Popma JJ, Steg G, Guyatt GH, Goodman SG (2008)
cular calciication, hyperkalemia, and arrhythmia, rather Antithrombotic therapy for non-ST-segment elevation acute cor-
than PLT aggregation and thrombosis. Aspirin resistance onarymsyndromes: American College of Chest Physicians Evi-
dence-Based Clinical Practice Guidelines [8th Edition]. Chest
(AR) and HPR may also contribute to these indings. Aksu
133:670S–707S
et al. [96] reported that AR was detected in 28 (51.9%) 4. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA,
patients before HD, whereas in 27 (50%) patients after Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB,
HD (p < 0.0001). The AR status was changed in 9 (16.6%) Rosenield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ,
White J, White RA, Antman EM, Smith SC Jr, Adams CD,
patients after HD. The authors concluded that the preva-
Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs
lence of AR in patients undergoing HD seems higher than AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC, AHA
in most other studied populations. Moreover, the AR sta- (2006) 2005 practice guidelines for the management of patients
tuses of a signiicant number of patients undergoing HD with peripheral arterial disease [lower extremity, renal, mes-
enteric, and abdominal aortic]: a collaborative report from the
may change after an HD session. Recently, Konishi et al.
American Association for Vascular Surgery/Society for Vascu-
[97] reported that, in a small group of HD patients with lar Surgery, Society for Cardiovascular Angiography and Inter-
stable angina treated with DES (n = 28), who were taking ventions, Society for Vascular Medicine and Biology, Society
aspirin and 75 mg clopidogrel, HD was associated with of Interventional Radiology, and the ACC/AHA Task Force on
Practice Guidelines [Writing Committee to Develop Guidelines
a HPR, which may contribute to the higher incidence of
for the Management of Patients with Peripheral Arterial Dis-
major adverse cardiac events at 1 year compared with 114 ease]: endorsed by the American Association of Cardiovascular
non-HD patients. and Pulmonary Rehabilitation; National Heart, Lung, and Blood
In conclusion, our review supports the Kidney Disease Institute; Society for Vascular Nursing; TransAtlantic Inter-Soci-
ety Consensus; and Vascular Disease Foundation. Circulation
Outcomes Quality Initiative (KDOQI) Clinical Practice
113:e463–e465
Guidelines for Cardiovascular Disease in Dialysis Patients, 5. Antithrombotic Trialists’ Collaboration (2002) Collaborative
which reported that there are no RCTs in dialysis patients metaanalysis of randomised trials of antiplatelet therapy for pre-
that establish the safety and eicacy of aspirin for primary vention of death, myocardial infarction, and stroke in high risk
patients. BMJ 324:71–78
or secondary prevention of atherosclerotic events. Since
6. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB,
CKD patients are among the highest-risk groups for ath- Moliterno DJ, O’Gara P, Whitlow P (2007) Prevention of prema-
erosclerotic events, it might be reasonable to use aspirin in ture discontinuation of dual antiplatelet therapy in patients with
HD patients who do not have contraindications for aspirin coronary artery stents: a science advisory from the American
Heart Association, American College of Cardiology, Society for
therapy. Moreover, DES or conventional stents should be
Cardiovascular Angiography and Interventions, American Col-
implemented according to local practice. The incidence of lege of Surgeons, and American Dental Association, with rep-
restenosis after PCI with DES is reduced in the non-dialy- resentation from the American College of Physicians. Catheter
sis population. As the risk of restenosis is higher in dialysis Cardiovasc Interv 69:334–340
7. King SB III, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK, Mor-
patients, the use of DES is favored. However, the bleeding
rison DA, Williams DO (2008) Writing Committee Members,
risk in HD patients needs to be strongly evaluated, espe- Feldman TE, Kern MJ, O’Neill WW, Schaf HV, Whitlow PL,
cially before starting dual AA treatment. Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger

13
J Nephrol

SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle 22. Hall R, Mazer CD (2011) Antiplatelet drugs: a review of their
BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy pharmacology and management in the perioperative period.
CW. 2007 focused update of the ACC/AHA/SCAI 2005 guide- Anesth Analg 112(2):292–318
line update for percutaneous coronary intervention: a report of 23. Schror K (1993) The basic pharmacology of ticlopidine and
the American College of Cardiology/American Heart Associa- clopidogrel. Platelets 4(5):252–261
tion Task Force on Practice Guidelines: 2007 Writing Group to 24. McTavish D, Faulds D, Goa KL (1990) Ticlopidine. An updated
Review New Evidence and Update the ACC/AHA/SCAI 2005 review of its pharmacology and therapeutic use in platelet-
Guideline Update for Percutaneous Coronary Intervention, dependent disorders. Drugs 40(2):238–259
Writing on Behalf of the 2005 Writing Committee. Circulation 25. Cattaneo M (2010) New P2Y[12] inhibitors. Circulation
117:261–295 121(1):171–179
8. Foley RN, Parfrey P, Samak MJ (1998) Clinical epidemiology 26. Taubert D, Kastrati A, Harlinger S, Gorchakova O, Lazar A, von
of cardiovascular disease in chronic renal failure. Am J Kidney Beckerath N, Scho¨mig A, Scho¨mig E (2004) Pharmacokinet-
Dis 32:S112–S119 ics of clopidogrel after administration of a high loading dose.
9. Jungers P, Khoa TN, Massy ZA, Zingraf J, LaBrunie M, Thromb Hemost 92:311–316
Descamps-Latscha B, Man NK. Incidence of atherosclerotic 27. Patrono C, Bachmann F, Baigent C, Bode C, Charbonnier B,
arterial occlusive accidents in predialysis and dialysis patients: De Caterina R, Fitzgerald D, Garcı´a Rodrı´guez LA, Hirsh J,
A multicentric study in the Ile de France district. Nephrol Dial Husted S, Kvasnicka J, Montalescot G, Verheugt F, Vermylen J,
Transplant 14:898–902, 1999 Wallentin L (2004) Expert Consensus document on the use of
10. U.S. Renal Data System. Bethesda, MD: National Institutes of antiplatelet agents. Eur Heart J 25:166–181
Health, National Institute of Diabetes and Digestive and Kid- 28. Mehta SR, Yusuf S, Peters RJ et al (9281) Efects of pretreat-
ney Diseases; 2013. USRDS 2013 Annual Data Report. ment with clopidogrel and aspirin followed by long-term therapy
11. Davì G, Patrono C (2007) Platelet activation and atherothrom- in patients undergoing percutaneous coronary intervention: the
bosis. N Engl J Med 357:2482–2494 PCI-CURE study. The Lancet 358:527–533
12. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, 29. randomised A, blinded (1996) trial of clopidogrel versus aspirin
DeMarco S, Tournier B, Vyas SN, FitzGerald GA (2001) in patients at risk of ischaemic events [CAPRIE]. CAPRIE Steer-
Cyclooxygenase inhibitors and the antiplatelet efects of aspi- ing Committee. The Lancet 348(9038):1329–1339
rin. N Engl J Med 345:1809–1817 30. Mega JL, Close SL, Wiviott SD et al (2009) Cytochrome p-450
13. Serebruany VL, Malinin AI, Eisert RM, Sane DC (2004) Risk polymorphisms and response to clopidogrel. N Engl J Med
of bleeding complications with antiplatelet agents: metaanaly- 360(4):354–362
sis of 338,191 patients enrolled in 50 randomized controlled 31. Cattaneo M (2007) Resistance to antiplatelet drugs: molecu-
trials. Am J Hematol 75:40–47 lar mechanisms and laboratory detection. J Thromb Hemost
14. Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, 5:230–237
Mertens BJ, Huisman MV (2007) Prevalence of persistent 32. Tassies D (2006) Pharmacogenetics of antithrombotic drugs.
platelet reactivity despite use of aspirin: a systematic review. Curr Pharm Des 12:2425–2435
Am Heart J 153:175–181 33. Siller-Matula J, Schror K, Wojta J, Huber K (2007) Thienopyri-
15. Eikelboom JW, Hankey GJ, Thom J, Bhatt DL, Steg PG, Mon- dine in cardiovascular disease: focus on clopidogrel resistance.
talescot G, Johnston SC, Steinhubl SR, Mak KH, Easton JD, Thromb Hemost 97:385–393
Hamm C, Hu T, Fox KA, Topol EJ (2008) Incomplete inhi- 34. Pena A, Collet JP, Hulot JS, Silvain J, Barthe´le´my O, Beygui F,
bition of thromboxane biosynthesis by acetylsalicylic acid: Funck-Brentano C, Montalescot G (2009) Can we override clopi-
determinants and efect on cardiovascular risk. Circulation dogrel resistance? Circulation 119:2854–2857
118:1705–1712 35. Gori AM, Marcucci R, Migliorini A, Valenti R, Moschi G, Pan-
16. Christiaens L, Macchi L (2007) Monitoring of the antiplatelet iccia R, Buonamici P, Gensini GF, Vergara R, Abbate R, Antoni-
drugs efect in patients with coronary artery disease: what is ucci D (2008) Incidence and clinical impact of dual nonrespon-
the real clinical impact? Curr Vasc Pharmacol 5:293–301 siveness to aspirin and clopidogrel in patients with drug-eluting
17. Golanski J, Golanski R, Chizynski K, Iwaszkiewicz A, Rozal- stents. J Am Coll Cardiol 52:734–739
ski M, Wieclawska B, Boncler M, Watala C (2001) Platelet 36. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry
hyperreactivity after coronary artery bypass grafting: the pos- US (2005) The relation of dosing to clopidogrel responsive-
sible relevance to glycoprotein polymorphisms—a preliminary ness and the incidence of high post-treatment platelet aggrega-
report. Platelets 12:241–247 tion in patients undergoing coronary stenting. J Am Coll Cardiol
18. Feher G, Feher A, Pusch G, Lupkovics G, Szapary L, Papp E 45:1392–1396
(2009) The genetics of antiplatelet drug resistance. Clin Genet 37. Fontana P, Senouf D, Mach F (2008) Biological efect of
75:1–18 increased maintenance dose of clopidogrel in cardiovascular out-
19. Cipollone F, Ciabattoni G, Patrignani P, Pasquale M, Di Gre- patients and inluence of the cytochrome P450 2C19*2 allele on
gorio D, Bucciarelli T, Davì G, Cuccurullo F, Patrono C (2000) clopidogrel responsiveness. Thromb Res 121:463–468
Oxidant stress and aspirin-insensitive thromboxane biosynthe- 38. Abuzahra M, Pillai M, Caldera A, Hartley WB, Gonzalez R,
sis in severe unstable angina. Circulation 102:1007–1013 Bobek J, Dokainish H, Lakkis N (2008) Comparison of higher
20. Zimmermann N, Kurt M, Wenk A, Winter J, Gams E, Hohlfeld clopidogrel loading and maintenance dose to standard dose on
T (2005) Is cardiopulmonary bypass a reason for aspirin resist- platelet function and outcomes after percutaneous coronary inter-
ance after coronary artery bypass grafting? Eur J Cardiothorac vention using drug-eluting stents. Am J Cardiol 102:401–403
Surg 27:606–610 39. Chintala M, Shimizu K, Ogawa M, Yamaguchi H, Doi M, Jensen
21. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao P (2008) Basic and translational research on proteinase-activated
T, Bray PF, Kleiman NS (2006) Aspirin and clopidogrel drug receptors: antagonism of the proteinase-activated receptor 1 for
response in patients undergoing percutaneous coronary inter- thrombin, a novel approach to antiplatelet therapy for athero-
vention: the role of dual drug resistance. J Am Coll Cardiol thrombotic disease. J Pharmacol Sci 108:433–438
47:27–33 40. Jakubowski JA, Winters KJ, Naganuma H, Wallentin L
(2007) Prasugrel: a novel thienopyridine antiplatelet agent. A

13
 J Nephrol

review of preclinical and clinical studies and the mechanistic 55. Cases A, Reverter JC, Escolar G et al (1993) Platelet activation
basis for its distinct antiplatelet proile. Cardiovasc Drug Rev on hemodialysis: inluence of dialysis membranes. Kidney Int
25:357–374 43(Suppl 41):S217–S220
41. Michelson AD, Frelinger AL III, Braunwald E, Downey WE, 56. Turitto VT, Hall CL (1998) Mechanical factors afecting
Angiolillo DJ, Xenopoulos NP, Jakubowski JA, Li Y, Murphy hemostasis and thrombosis. Thromb Res 92:S25–S31
SA, Qin J, McCabe CH, Antman EM, Wiviott SD (2009) for 57. Viener A, Aviram M, Better OS, Brook JG (1986) Enhanced
the TRITON-TIMI 38 Investigators. Pharmacodynamic assess- in vitro platelet aggregation in hemodialysis patients. Nephron
ment of platelet inhibition by prasugrel vs. clopidogrel in the 43:139–143
TRITON-TIMI 38 trial. Eur Heart J 30:1753–1763 58. Savage B, Ruggeri ZM (1991) Selective recognition of adhe-
42. Antman EM, Wiviott SD, Murphy SA, Voitk J, Hasin Y, sive sites in surface-bound ibrinogen by glycoprotein IIb-IIIa
Widimsky P, Chandna H, Macias W, McCabe CH, Braunwald on nonactivated platelets. J Biol Chem 266:11227–11233
E (2008) Early and late beneits of prasugrel in patients with 59. Sagripanti A, Cupisti A, Baicchi U, Ferdeghini M, Morelli
acute coronary syndromes undergoing percutaneous coronary E, Barsotti G (1993) Plasma parameters of the prothrombotic
intervention: a TRITON-TIMI 38 [TRial to Assess Improve- state in chronic uremia. Nephron 63:273–278
ment in Therapeutic Outcomes by Optimizing Platelet Inhibi- 60. Tomura S, Nakamura Y, Deguchi F, Ando R, Chida Y,
tioN with Prasugrel-Thrombolysis In Myocardial Infarction] Marumo F (1991) Coagulation and ibrinolysis in patients
analysis. J Am Coll Cardiol 51:2028–2033 with chronic renal failure undergoing conservative treatment.
43. Knobl P, Jilma B, Gilbert JC, Hutabarat RM, Wagner PG, Thromb Res 64:81–90
Jilma- Stohlawetz P (2009) Anti-von Willebrand factor 61. Lai KN, Yin JA, Yuen PM, Li PK (1991) Efect of hemodialy-
aptamer ARC1779 for refractory thrombotic thrombocytopenic sis on protein C, protein S, and antithrombin III levels. Am J
purpura. Transfusion 49(10):2181–2185 Kidney Dis 17:38–42
44. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson 62. LeSar CJ, Merrick HW, Smith MR (1999) Thrombotic compli-
H, Held C, Horrow J, Husted S, James S, Katus H, Mahafey cations resulting from hypercoagulable states in chronic hemo-
KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington dialysis vascular access. J Am Coll Surg 189:73–79
RA; PLATO Investigators, Freij A, Thorsén M (2009) Tica- 63. Brunet P, Aillaud MF, San Marco M et al (1995) Antiphos-
grelor versus clopidogrel in patients with acute coronary syn- pholipids in hemodialysis patients: relationship between lupus
dromes. N Engl J Med 361(11):1045–1057 anticoagulant and thrombosis. Kidney Int 48:794–800
45. Schror K (2002) The pharmacology of cilostazol. Diabetes 64. Sood M, Larkina M, Thumma J et al (2013) Major bleeding
Obes Metab 4(Suppl 2):S14–S19 events and risk stratiication of antithrombotic agents in hemo-
46. Suh JW, Lee SP, Park KW et al (2011) Multicenter rand- dialysis: results from the DOPPS. Kidney Int 84:600–608
omized trial evaluating the eicacy of cilostazol on ischemic 65. Trespalacios FC, Taylor AJ, Agodoa LY, Abbott KC (2002)
vascular complications after drug-eluting stent implantation Incident acute coronary syndromes in chronic dialysis patients
for coronary heart disease: results of the CILON-T [inluence in the United States. Kidney Int 62:1799–1805
of CILostazol-based triple antiplatelet therapy ON ischemic 66. Geara AS, Azzi N, Bassil C, El-Sayegh S (2010) Aspirin
complication after drug-eluting stenT implantation] trial. J Am resistance in hemodialysis patients. Int Urol Nephrol 44:325
Coll Cardiol 57(3):280–289 67. Ethier J, Bragg-Gresham JL, Piera L, Akizawa T, Asano Y,
47. Angiolillo DJ, Capranzano P, Goto S et al (2008) A rand- Mason N, Gillespie BW, Young EW (2007) Aspirin prescrip-
omized study assessing the impact of cilostazol on platelet tion and outcomes in hemodialysis patients: the Dialysis Out-
function proiles in patients with diabetes mellitus and coro- comes and Practice Patterns Study [DOPPS]. Am J Kidney Dis
nary artery disease on dual antiplatelet therapy: results of the 50(4):602–611
OPTIMUS-2 study. Eur Heart J 29(18):2202–2211 68. Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V
48. Aktas B, Utz A, Hoenig-Liedl P, Walter U, Geiger J (2003) et al (2013) Antiplatelet agents for chronic kidney disease.
Dipyridamole enhances NO/Cgmp-mediated vasodilator- Cochrane Database Syst Rev 2:CD008834
stimulated phosphoprotein phosphorylation and signaling in 69. Berger AK, Duval S, Krumholz HM (2003) Aspirin, beta-
human platelets: in vitro and in vivo/ex vivo studies. Stroke blocker, and angiotensin-converting enzyme inhibitor therapy
34(3):764–769 in patients with end-stage renal disease and an acute myocar-
49. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal dial infarction. J Am Coll Cardiol 42:201–208
A (1996) European Stroke Prevention Study. 2. Dipyridamole 70. McCullough PA, Sandberg KR, Borzak S, Hudson MP, Garg
and acetylsalicylic acid in the secondary prevention of stroke. J M, Manley HJ (2002) Beneits of aspirin and beta-blockade
Neurol Sci 143(1–2):1–13 after myocardial infarction in patients with chronic kidney dis-
50. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A ease. Am Heart J 144:226–232
(2006) Aspirin plus dipyridamole versus aspirin alone after cere- 71. Sanchez Perales MC, Vazquez E, Garcia Cortes MJ, Borrego
bral ischemia of arterial origin [ESPRIT]: randomised controlled FJ, Borrego J, Perez del Barrio P et al (2002) Platelet antiag-
trial. The Lancet 367(9523):1665–1673 gregation and hemorrhagic risk in hemodialysis. Nefrologia
51. Sloand JA, Sloand EM (1997) Studies on platelet membrane gly- 22(5):456–462
coproteins and platelet function during hemodialysis. J Am Soc 72. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland
Nephrol 8:799–803 JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP,
52. Benigni A, Boccardo P, Galbusera M et al (1993) Reversible Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P,
activation defect of the platelet glycoprotein IIb-IIIa complex in Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM,
patients with uremia. Am J Kidney Dis 22:668–676 Ruschitzka F, Rutten FH, van der Meer P (2016) 2016 ESC
53. Liani M, Salvati F, Tresca E et al (1996) Arteriovenous istula Guidelines for the diagnosis and treatment of acute and chronic
obstruction and expression of platelet receptors for von Wille- heart failure. Kardiol Pol 74(10):1037–1147
brand factor and for ibrinogen (glycoproteins GPIb and GPIIb/ 73. Summaria F, Giannico MB, Talarico M, Patrizi R (2015) Anti-
IIIa) in hemodialysis patients. Int J Artif Organs 19:451–454 platelet Therapy in Hemodialysis Patients Undergoing Percuta-
54. Hakim RM, Schafer AI (1985) Hemodialysis-associated platelet neous Coronary Interventions. Nephro Urol Mon 7(4):e28099
activation and thrombocytopenia. Am J Med 78:575–580

13
J Nephrol

74. Chertow GM, Normand SL, McNeil BJ (2004) “Renal- Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W,
ism”: inappropriately low rates of coronary angiography in Gurbel PA (2009) Association of cytochrome P450 2C19 gen-
elderly individuals with renal insuiciency. J Am Soc Nephrol otype with the antiplatelet efect and clinical eicacy of clopi-
15(9):2462–2468 dogrel therapy. JAMA 302:849–857
75. Hemmelgarn BR, Southern D, Culleton BF, Mitchell LB, Knudt- 86. Holden RM, Harman GJ, Wang M, Holland D, Day AG (2008)
son ML, Ghali WA et al (2004) Survival after coronary revas- Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol
cularization among patients with kidney disease. Circulation 3(1):105–110
110(14):1890–1895 87. Kaufman JS, O’Connor TZ, Zhang JH, Cronin RE, Fiore LD,
76. Reddan DN, Szczech LA, Tuttle RH, Shaw LK, Jones RH, Ganz MB, Goldfarb DS, Peduzzi PN (2003) Veterans Afairs
Schwab SJ et al (2003) Chronic kidney disease, mortality, and Cooperative Study Group on Hemodialysis Access Graft Throm-
treatment strategies among patients with clinically signiicant bosis. Randomized controlled trial of clopidogrel plus aspirin to
coronary artery disease. J Am Soc Nephrol 14(9):2373–2380 prevent hemodialysis access graft thrombosis. J Am Soc Nephrol
77. Chang TI, Shilane D, Kazi DS, Montez-Rath ME, Hlatky MA, 14(9):2313–2321
Winkelmayer WC (2012) Multivessel coronary artery bypass 88. O’Hare AM (2005) Management of peripheral arterial disease in
grafting versus percutaneous coronary intervention in ESRD. J chronic kidney disease. Cardiol Clin 23(3):225–236
Am Soc Nephrol 23(12):2042–2049 89. Franczyk B, Gluba-Brzózka A, Ciałkowska-Rysz A, Banach M,
78. Authors/Task Force M, Windecker S, Kolh P, Alfonso F, Collet Rysz J (2016) The Problem of Atrial Fibrillation in Patients with
JP, Cremer J, et al (2014) 2014 ESC/EACTS Guidelines on myo- Chronic Kidney Disease. Curr Vasc Pharmacol 14(3):260–265
cardial revascularization: The Task Force on Myocardial Revas- 90. Kim SJ, Bang OY (2013) Antiplatelet therapy for preventing
cularization of the European Society of Cardiology [ESC] and stroke in patients with chronic kidney disease. Contrib Nephrol
the European Association for Cardio-Thoracic Surgery [EACTS] 179:119–129
Developed with the special contribution of the European Asso- 91. Hiremath S, Holden RM, Fergusson D, Zimmerman DL (2009)
ciation of Percutaneous Cardiovascular Interventions [EAPCI]. Antiplatelet medications in hemodialysis patients: a systematic
Eur Heart J 35(37):2541–2619 review of bleeding rates. Clin J Am Soc Nephrol 4(8):1347–1355
79. Tsai TT, Messenger JC, Brennan JM, Patel UD, Dai D, Piana RN 92. Panichi V, Rizza GM, Paoletti S, Bigazzi R, Aloisi M, Barsotti
et al (2011) Safety and eicacy of drug-eluting stents in older G, Rindi P, Donati G, Antonelli A, Panicucci E, Tripepi G, Tetta
patients with chronic kidney disease: a report from the linked C, Palla R; RISCAVID Study Group (2008) Chronic inlam-
CathPCI Registry-CMS claims database. J Am Coll Cardiol mation and mortality in hemodialysis: efect of diferent renal
58(18):1859–1869 replacement therapies. Results from the RISCAVID study. Neph-
80. Shenoy C, Boura J, Orshaw P, Harjai KJ (2010) Drug-eluting rol Dial Transplant 23(7):2337–2343
stents in patients with chronic kidney disease: a prospective reg- 93. Palmer SC, Di Micco L, Razavian M, Craig JC, Ravani P, Perko-
istry study. PLoS One 5(11):e15070 vic V, Tognoni G, Graziano G, Jardine M, Pellegrini F, Nicolucci
81. Fourtounas C, Panagiotou A (2013) Oral Antiplatelet Agents in A, Webster A, Strippoli GF (2013) Antiplatelet therapy to pre-
Dialysis Patients: Friends or Foes? Gen Med 1:3 vent hemodialysis vascular access failure: systematic review and
82. Alexopoulos D, Panagiotou A, Xanthopoulou I, Komnina- meta-analysis. Am J Kidney Dis 61(1):112–122
kis D, Kassimis G, Davlouros P, Fourtounas C, Goumenos DJ 94. Coleman CI, Tuttle LA, Teevan C, Baker WL, White CM, Rein-
(2011) Antiplatelet efects of prasugrel vs. double clopidogrel hart KM (2010) Antiplatelet agents for the prevention of arterio-
in patients on hemodialysis and with high on-treatment platelet venous istula and graft thrombosis: a meta analysis. Int J Clin
reactivity. Thromb Hemost 9(12):2379–2385 Pract 64(9):1239–1244
83. Alexopoulos D, Dimitropoulos G, Davlouros P, Xanthopoulou 95. Wang Y, Ivany JN, Perkovic V, Gallagher MP, Woodward M,
I, Kassimis G, Stavrou EF, Hahalis G, Athanassiadou A (2011) Jardine MJ (2016) Anticoagulants and antiplatelet agents for
Prasugrel overcomes high on-clopidogrel platelet reactivity post- preventing central venous hemodialysis catheter malfunction in
stenting more efectively than high-dose [150-mg] clopidogrel: patients with end-stage kidney disease. Cochrane Database Syst
the importance of CYP2C19*2 genotyping. JACC Cardiovasc Rev 4:CD009631
Interv 4:403–410 96. Aksu et al (2015) Aspirin resistance in patients undergoing
84. James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, hemodialysis and efect of hemodialysis on aspirin resistance.
Harrington RA, Horrow J, Katus H, Keltai M, Lewis BS, Parikh Clin Appl Thromb Hemost 21(1):82–86
K, Storey RF, Szummer K, Wojdyla D, Wallentin L (2010) Tica- 97. Konishi A, Shinke T, Otake H, Takaya T, Osue T, Kinutani H,
grelor vs. clopidogrel in acute coronary syndromes in relation Kuroda M, Takahashi H, Terashita D, Hirata K (2016) Impact
to renal function: results from the Platelet Inhibition and Patient of residual platelet reactivity under clopidogrel treatment for
Outcomes [PLATO] trial. Circulation 122:1056–1067 lesions and the clinical outcome after drug-eluting stent implan-
85. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, tation in patients with hemodialysis. J Cardiol 67(6):531–537
Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q,

13