Introduction
With a decline in kidney function, thromboembolic and cardiovascular complications increase and affect approximately half of patients with CKD stage 4–5 (1,2). This may, at least in part, be caused by platelet dysfunction. Platelets not only drive the formation of atherosclerotic lesions (3) but, through pathologic thrombus formation, also trigger ischemic events such as myocardial infarction (4).
Counterintuitively, patients with CKD are also at a 2.3-fold higher risk of hemorrhages, which increases to a 3.5-fold higher bleeding risk in patients with CKD with kidney failure (CKD stage 5D, CKD5D) (5,6). Approximately one out of seven patients with kidney failure will experience major bleeding complications within 3 years after initiation of hemodialysis (7). In particular, gastrointestinal, intracranial, and percutaneous coronary intervention (PCI) procedure-related bleeding complications are common in patients with CKD5D (8,9).
Given the high clinical relevance of thrombosis and bleeding in patients with CKD, this review provides insights into altered hemostasis in CKD and underlying mechanisms, with a focus on platelet abnormalities. Also, antiplatelet therapies are discussed regarding risk versus benefit consideration in terms of cardiovascular outcome versus bleeding risk. Altogether, this review aims to support further research of altered platelet function and antiplatelet therapy in patients with CKD.
Platelet Function in Hemostasis
Platelet adhesion and aggregation are well-coordinated processes (Figure 1A) (10). In healthy conditions, the endothelium counteracts interaction with circulating platelets, platelet activation, and clot formation by producing nitric oxide and prostacyclin, which both inhibit platelet activation by raising intracellular levels of cyclic guanosine monophosphate and cAMP, respectively (11,12). Also, endothelial cells express the ecto-nucleases CD39 and CD73, and thereby contribute to the degradation of the platelet agonists ADP and ATP into the platelet inhibitor adenosine (13).
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Figure 1.: The process of thrombus formation and summary of CKD-induced platelet abnormalities and contributing factors. (A) Whereas healthy endothelium protects from platelet adhesion and activation, vascular injury triggers the formation of thrombi through platelet adhesion, activation, and aggregation. Furthermore, tissue factor exposed by the injured vessel wall triggers the production of thrombin, which converts fibrinogen to fibrin, resulting in the formation of a stable, fibrin-rich clot. (B) Besides a reduction in platelet number in patients with CKD, alterations have been described in stimulation-induced platelet adhesion, aggregation, granule secretion, thromboxane A2 (TXA2) generation, and platelet-mediated clot retraction. CKD may directly affect platelet responses and thrombus formation in CKD through uremic toxin accumulation and a chronic low-grade inflammation, and indirectly through dialysis, vascular inflammation, and reduced vascular integrity, hypercoagulability, and anemia. For more details, see text. Ca2+, calcium; Fg, fibrinogen; GPIb-V-IX, glycoprotein Ib-V-IX; GPVI, glycoprotein VI; NO, nitric oxide; PAR1/4, protease-activated receptor 1/4; TP, thromboxane receptor; TXA2, thromboxane A2; α 2, α 2 adrenergic receptor; α and δ granules, alpha and dense granules.
On vascular injury, platelet inhibitory properties of the endothelium can be lost (Figure 1A). Reduced endothelial integrity triggers exposure of platelets to vWf, collagens, and other proteins within the extracellular matrix underneath the endothelium. Platelet binding to vWf (via glycoprotein Ib-V-IX complexes) (14) and subsequently collagen (via glycoprotein VI and integrin α2β1 receptors) (15,16) triggers the secretion of autocrine and paracrine molecules from the platelet α granules (e.g., fibrinogen, platelet factor 4) and dense granules (e.g., ADP, ATP) (17). Further, thromboxane A2 is synthesized and released by platelets. Thromboxane A2, ATP, and ADP recruit more platelets to the growing thrombus and amplify the initial triggers for platelet activation via the thromboxane receptor, P2X1/P2Y1 and P2Y12 receptors, respectively (11). A conformational change in the integrin αIIbβ3 receptors on the platelet surface supports fibrinogen binding and mediates platelet-platelet aggregation (18).
Tissue factor exposed by the damaged vessel wall initiates thrombin formation and subsequent coagulation by activating the extrinsic pathway of coagulation (19). Within the thrombus, highly activated platelets provide a procoagulant surface for the assembly of the prothrombinase complex, and thereby further support thrombin generation. This amplifies platelet activation and leads to the formation of fibrin, thus forming a dense fibrin network that stabilizes the thrombus (19,20). Thus, a close interplay between platelets and the coagulation system ensures the formation of stable fibrin-rich clots (20).
Platelet Abnormalities in CKD
In patients with CKD, besides a reduction in platelet number, multiple abnormalities in platelet function have been demonstrated (Figure 1B). Given that platelets are central to hemostasis, abnormalities in platelet function resulting in either platelet hyper- or hyporeactivity may contribute to the development of thrombotic or hemorrhagic complications.
Platelet Number
In patients with CKD not receiving dialysis, the majority of studies do not find a significant reduction in platelet number (21). In patients with CKD5D, however, platelet number can by reduced by up to approximately 20% (5,22–24). This could either be a result of continuous platelet consumption by ongoing activation (e.g., by extracorporal circulation under repeated hemodialysis, which can induce platelet aggregation, secretion, and platelet-leukocyte aggregate formation due to shear stress in the extracorporeal circuit and exposure to the dialysis membrane [25,26]) or result from a reduced platelet production by megakaryocytes. A decrease in the amount of newly formed platelets, the so-called reticulated platelets, was found in patients on hemodialysis (4%) compared with controls (9%) (27), with reticulated platelets detected using nucleic acid–staining dyes. However, these results may have to be interpreted with caution because these dyes also bind to nucleotides within the platelet dense granules (28,29), of which nucleotide content changes in CKD (as discussed below) (30,31). Thus, whether the reduction in platelet count in patients with CKD5D is the result of insufficient production (27,32) or rather increased consumption requires further clarification.
Platelet counts have to be severely reduced to cause spontaneous bleeding (<5×109/L in patients who are clinically stable, a reduction of >95%) (33). Furthermore, mouse models of CKD display a prolonged bleeding time without a significant decline in platelet numbers (34). Combined, this suggests the reduction in platelet number by itself does not appear to be solely responsible for the hemorrhagic complications in CKD.
Platelet Function
A variety of anomalies in platelet function have been reported in CKD (Figure 1B). A decreased adhesiveness and aggregation of platelets from patients with CKD who are nondialyzed has already been reported >40 years ago (35,36), with the majority of studies showing a decreased platelet aggregation in CKD on collagen, ADP, AA, or epinephrine stimulation (35,37–40). A reduction in ADP-mediated platelet aggregation in nondialysis-dependent CKD was more pronounced for the more uremic individuals (40). Also, the aggregation response toward collagen/epinephrine and collagen/ADP under flow was reduced in patients with nondialyzed CKD5 (41). Other abnormalities in platelet function reported in patients with CKD who are conservatively treated include reduced thromboxane production (42) and increased nitric oxide production (43). In patients with CKD on maintenance hemodialysis, a decrease in ADP-induced platelet aggregation (27) and platelet-mediated clot retraction (44) was shown.
At first glance, these defects in platelet function in CKD appear to agree with platelet hyporeactivity and a corresponding bleeding phenotype in patients with CKD. However, other studies report a normal to increased aggregation response to a multitude of platelet agonists in patients with CKD who are conservatively treated (27,41,43,45–47) and in patients with CKD on dialysis (41,45,48). Further, dense granules display a reduced ADP and serotonin content in CKD (30), being more pronounced in patients with CKD5D compared with patients with CKD not receiving dialysis (31). This, together with elevated basal cytosolic Ca2+ levels (45) and increased plasma levels of P-selectin as platelet activation marker (49), may suggest that platelets in CKD have been increasingly preactivated.
An explanation for this apparent discrepancy could be the occurrence of platelet exhaustion in CKD, a concept whereby extensive platelet activation in pathophysiological conditions results in a secondary loss of function (50). Alternatively, heterogeneity in disease severity and existing comorbidities could underlay the apparent discrepancy in reported effects of CKD on platelets. Also, although the above-mentioned studies examined platelet activation mostly in platelet-rich plasma, to our knowledge, there are no studies available that have directly compared platelet function using isolated, washed platelets versus platelet-rich plasma to distinguish between potential platelet-intrinsic versus extrinsic effects of the uremic milieu on platelet function. Further, a clinical study along CKD stage 3–5D in which the many aspects of platelet function are studied simultaneously, including platelet function under flow conditions and plasma markers of platelet activation, could aid in providing more insight into CKD-induced platelet dysfunction.
Factors Contributing to Altered Hemostasis in CKD
CKD may directly affect platelets through the accumulation of uremic toxins and a chronic state of low-grade inflammation but may also indirectly affect platelets and thrombus formation through vascular inflammation and reduced vascular integrity, hypercoagulability, anemia, and dialysis (Figure 1B). For the effect of dialysis on platelets and hemostasis, as introduced above, we refer to another comprehensive review (25).
Uremic Toxin Accumulation and Chronic Low-Grade Inflammation in CKD
Due to a gradual decline in kidney filtration function, uremic retention solutes (also named uremic toxins) accumulate in patients with CKD (51). Several of these uremic toxins have been shown to alter platelet reactivity, with either inhibitory or stimulatory influences on platelet responsiveness identified. On the one hand, the polyamines spermidine, spermine, and putrescine have been shown to impair platelet responsiveness as analyzed by platelet aggregation, secretion, and thromboxane synthesis (52–55). On the other hand, the uremic toxins trimethylamine N-oxide and indoxyl sulfate have strong prothrombotic effects in vitro and in vivo (56,57). Still, the overall effect of the uremic milieu on hemostasis remains unclear, as to date, >130 uremic toxins are identified to be increased in CKD (58), and most of these are not yet examined for potential effects on platelets. The finding of a partial correction of reduced platelet aggregation after dialysis may support a concept of uremic toxin–induced platelet dysfunction (59). To which extent platelet dysfunction in patients with CKD5D is a consequence of kidney failure and the uremic milieu versus repeated dialysis requires further investigation.
Furthermore, in addition to uremic toxin accumulation, patients with CKD frequently demonstrate a state of chronic, low-grade inflammation (60). Because a proinflammatory milieu has been associated with platelet hyperreactivity (61,62) and even a decreased response to antiplatelet therapy (62), chronic low-level inflammation may also affect platelet function in CKD.
Endothelial Activation and Reduced Vascular Integrity in CKD
Progressive loss of kidney function triggers increased endothelial activation and inflammation, reduced endothelial proliferation and enhanced senescence, and reduced endothelial integrity and increased permeability, as previously discussed in more detail (63–65). Such CKD-induced changes of the endothelium accelerate atherosclerosis and render existing plaques more vulnerable to destabilization and thrombotic complications (63,64). Also, endothelial injury contributes to platelet activation and aggregation, and thereby thrombus formation (Figure 1A). Already in patients with CKD stage 3b–4, endothelial activation can be observed, reflected by increased plasma levels of active vWf, an important mediator during thrombus formation (see Platelet Function in Hemostasis) (66). Furthermore, uremic toxins, such as indoxyl sulfate and indole-3 acetic acid, directly increase the prothrombotic activity of the endothelium as reflected by increased tissue factor expression and activity (67,68).
In addition to the higher thrombotic risk, disruption of vascular integrity may contribute to bleeding, as is, for example, seen in inflammatory conditions in patients where platelet function is insufficient to secure vascular integrity (69). Combined, CKD induces endothelial changes that may contribute both to a higher thrombotic and bleeding risk in CKD.
Hypercoagulability in CKD
Activation of the coagulation system on vascular injury results in consolidation of the platelet plug by fibrin formation. Patients with CKD who are conservatively treated and patients on hemodialysis present with hypercoagulability characterized by elevated levels of tissue factor, fibrinogen, D-dimer, Factor VIII, tissue plasminogen activator, and thrombin-antithrombin complexes (70–73), and reduced levels of the anticoagulant proteins, protein C and S (74,75). Moreover, fibrin clots formed in plasma from patients on hemodialysis show a denser prothrombotic structure and reduced permeability, associated with a higher cardiovascular mortality risk (76–78). In parallel, fibrinogen of hemodialysis patients reveal post-translational glycosylation and guanidinylation, the latter resulting in the formation of thinner fibrin fibers (78). Combined, CKD-induced changes in the coagulation system translate into hypercoagulability and the formation of denser clots.
Anemia in CKD
A decrease in erythrocyte number and function results in less margination of platelets toward the vessel wall, with the latter process contributing to platelet adhesion and aggregation on the vessel wall. In contrast, a lower erythrocyte number triggers less scavenging of the platelet inhibitor nitric oxide by erythrocytes (79–81). In this way, anemia might contribute to both bleeding and thrombotic risk. The erythrocyte number decreases on CKD progression (on average approximately 13% reduction in CKD4, approximately 28% reduction in hemoglobin levels in CKD5D) (24), caused by a reduced synthesis of erythropoietin in the diseased kidney (82), uremic toxin–mediated inhibition of erythropoiesis (82,83), and a reduced lifespan of uremic erythrocytes (84,85).
In patients with CKD5D, the erythrocyte number is negatively correlated with bleeding time (86). However, partial or complete correction of anemia by administration of erythropoietin had no beneficial or even adverse effects on cardiovascular risk in patients with nondialysis CKD (87–89). In contrast, higher levels of residual platelet activity on antiplatelet-treatment were found in patients with anemia (90), both in patients with CKD stage 3b or beyond, and in patients without CKD (91). Such high on-treatment platelet reactivity indicates a poorer response to antiplatelet therapy and is associated with a greater risk of ischemic events after PCI (92).
Combined, an anemic condition as prevalent in patients with CKD may aggravate the consequences of platelet abnormalities in CKD.
Management of Thrombotic Risk in CKD with Antiplatelet Therapy
The predominantly clinically used platelet inhibitors for reducing thrombotic risk are acetylsalicylic acid and P2Y12 inhibitors, which interfere in the feed-forward amplification of platelet activation (Figure 2A) and are discussed in detail below. Unfortunately, patients with CKD, particularly those with stage ≥CKD4, are often underrepresented or even excluded from major clinical trials that assessed antiplatelet therapies (Figure 3). Therefore, current experience with antiplatelet therapy in CKD is mainly derived from underpowered post hoc subgroup analyses or large registries (93,94).
Figure 2.: Working mechanism of antiplatelet drugs. (A) Antiplatelet drugs reduce platelet activation by either preventing thromboxane A2 synthesis, inhibiting P2Y12 signaling, or increasing intraplatelet levels of cAMP and cyclic guanosine monophosphate. Also interfering with thrombin signaling (by blocking the thrombin receptor protease-activated receptor 1 (PAR-1) or interfering with thrombin production) can have antiplatelet effects. (B) Schematic overview of the effect of the different antiplatelet agents on cardiovascular risk and bleeding risk in CKD, and on efficacy (in terms of cardiovascular risk reduction) and HTPR in patients with CKD compared with patients without CKD. For more details, see text. cGMP, cyclic guanosine monophosphate; CV risk, cardiovascular risk; HTPR, high on-treatment platelet reactivity; PGH2, prostaglandin H2; PDE, phosphodiesterase; TP, thromboxane receptor; TXA2, thromboxane A2.
Figure 3.: Underrepresentation of patients with CKD ≥4 from clinical trials investigating the efficacy of P2Y 12 inhibitors. For randomized controlled trials (A) and observational studies (B) examining P2Y12 antiplatelet therapy, the number of included patients were categorized according to CKD stadium. Studies that excluded patients requiring dialysis are indicated with an asterisk (*).
Of note, alternative antiplatelet strategies include inhibition of 3′,5′-cyclonucleotid phosphodiesterase by cilostazol and dipyridamole (95–98) (Figure 2B), but require additional clinical trials before justifying clinical application in CKD. Also, with thrombin directly stimulating platelet activation through the protease-activated receptor 1 (PAR-1) and PAR-4, novel PAR-1 antagonists (e.g., vorapaxar) (99) and anticoagulation strategies blocking thrombin production or activity (e.g., Factor Xa and thrombin inhibitors) have an antiplatelet effect as well (100), although are not the focus of this review.
Acetylsalicylic Acid
Working Mechanism and Efficacy of Platelet Inhibition in CKD
Acetylsalicylic acid (aspirin) inhibits thromboxane production by irreversibly inhibiting platelet cyclooxygenase 1 (Figure 2A) (101). In CKD, the efficacy of platelet inhibition by acetylsalicylic acid has been controversially described: higher residual thromboxane synthesis and increased aggregation upon AA stimulation in patients with acetylsalicylic acid–treated CKD3–4 have been reported (102,103), whereas others found a comparable response to acetylsalicylic acid in terms of platelet aggregation in patients who are asymptomatic with nondialysis CKD stage 4–5 compared with patients with normal kidney function (104). Further, Remuzzi et al. reported in 1983 a functional cyclooxygenase defect in CKD platelets, possibly affecting the efficiency by which acetylsalicylic acid can inhibit platelet function (105).
Effect on Cardiovascular and Bleeding Risk in CKD
Acetylsalicylic acid constitutes the mainstay of antiplatelet therapy in daily practice, and lifelong therapy is recommended in patients with coronary artery disease (106,107). A Cochrane review from 2013 on the use of acetylsalicylic acid for primary and/or secondary prevention in patients with CKD concluded on a significant risk reduction for myocardial infarction, although with mortality rates unchanged and a higher rate of major and minor bleedings (108).
In contrast, acetylsalicylic acid administration for primary prevention of cardiovascular events is not indicated in CKD (109,110), with contrasting results reported in terms of cardiovascular benefit versus bleeding risk (Table 1) (111–114). A large interventional clinical trial is being undertaken to examine the effect of 75 mg acetylsalicylic acid daily on the primary prevention of cardiovascular complications, bleeding, and CKD progression in patients with CKD stage 3–4 (ATTACK, NCT03796156).
Table 1. -
Acetylsalicylic acid administration for primary prevention of cardiovascular events in chronic kidney disease
| Study |
Drug |
Study Type |
Patient Inclusion |
Cardiovascular Effect |
Bleeding Risk |
Reference |
| AASER (2018) |
ASA |
RCT |
116 patients without previous CV events with CKD3 or 4. Patients were randomly assigned to receive 100 mg ASA/day (n=54) or standard care (n=62) |
Incidence of CV events:
Standard=28%
ASA=10%
HR of CV events: 0.396 (0.146 to 1.076, P=0.07)
ASA significantly reduced the risk of coronary events: log-rank: 5.997, P=0.01 |
No differences in minor bleeding episodes, no major bleeding registered |
(111) |
| Liu J. et al. 2016 |
ASA |
Prospective cohort study |
406 patients on regular hemodialysis, of whom 152 patients received 100 mg ASA/day. Comparison cohort: 254 propensity-matched patients on hemodialysis not receiving ASA within the follow-up period |
RR of mortality
(ASA versus non-ASA):
Congestive HF: 1.01 (0.948 to 1.075)
MI: 0.627 (0.169 to 2.326)
RR of nonfatal events (ASA versus non-ASA):
Congestive HF: 1.114 (0.692 to 1.793)
CHD: 0.836 (0.454 to 1.537)
MI: 1.00 (0.96 to 1.041) |
No difference in cerebral hemorrhage:
RR (ASA versus non-ASA): 0.557 (0.21 to 1.50) |
(112) |
| Major R. et al. 2016 |
ASA |
Meta-analysis |
4469 patients with non-CKD5 and no history of CVD: 2241 patients on ASA treatment, 2228 patients received placebo |
RR of:
CVD: 0.92 (0.49 to 1.73)
CHD: 0.79 (0.34 to 1.87) |
RR of:
Minor bleeding: 2.70 (1.66 to 4.39)
Major bleeding: 1.98 (1.11 to 3.52) |
(113) |
| Qu B. et al. 2020 |
ASA |
Meta-analysis |
38,341 patients with CKD:
8345 patients with CKD3–4
1310 patients with CKD5
28,686 patients with CKD on HD |
RR of:
CVD: 0.96 (0.76 to 1.13)
HF: 0.91 (0.43 to 1.90)
MI: 0.72 (0.40 to 1.30)
CV mortality: 0.80 (0.60 to 1.07) |
RR of:
Minor bleeding: 2.57 (1.60 to 4.13)
Major bleeding: 1.15 (0.78 to 1.69) |
(114) |
95% confidence intervals are indicated in parentheses. ASA, acetylsalicylic acid; RCT, randomized controlled trial; CV, cardiovascular; HR, hazard risk; HF, heart failure; MI, myocardial infarction; RR, relative risk; CHD, coronary heart disease; CVD, cardiovascular disease; HD, hemodialysis.
Summary
In summary, acetylsalicylic acid is the mainstay for secondary prevention of cardiovascular events in patients with CKD, although with a higher bleeding risk reported and with conflicting reports on a potentially lower platelet-inhibiting efficiency in CKD compared with patients without CKD (Figure 2B).
P2Y12 Inhibitors
Working Mechanism and Application in CKD
The P2Y12 receptor inhibitors block ADP-induced platelet activation (Figure 2A), as for the thienopyridines clopidogrel and prasugrel (irreversible, competitive inhibitors) and the cyclo-pentyltriazolo-pyrimidine ticagrelor (reversible, noncompetitive inhibitor) (115). They are predominantly used in combination with acetylsalicylic acid as dual antiplatelet therapy after stent implantation (116). Presently, American Heart Association and European Society of Cardiology guidelines do not provide specific guidelines for dual antiplatelet therapy in patients with CKD: in general, a similar treatment duration is recommended as for patients without CKD, although alternative treatment modalities (e.g., duration on the basis of dual antiplatelet therapy score) are encouraged but not recommended (117,118). Currently, there are no recommendations for dose adjustment of the P2Y12 inhibitors in CKD (119–121).
Effect on Cardiovascular and Bleeding Risk in CKD and Residual “On-Treatment” Platelet Reactivity
Even under dual antiplatelet therapy, cardiovascular risk remains higher in patients with CKD compared with patients with normal kidney function (Table 2) (93,94,122–124). A post hoc analysis of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial (randomized controlled trial [RCT] with patients with acute coronary syndrome [ACS] treated with clopidogrel versus placebo) concluded that clopidogrel reduces cardiovascular risk (cardiovascular death, myocardial infarction, or stroke) both in patients with healthy kidney function and in patients with (mild to moderate) CKD (125). However, clopidogrel may not provide the same benefit in terms of relative and/or absolute cardiovascular risk reduction (including cardiovascular death, myocardial infarction, or stroke) in patients with GFR <60 ml/min per 1.73 m2 compared with patients with healthy kidney function, and even comes at the expense of a higher bleeding risk in CKD, as concluded from a post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial (RCT with patients undergoing PCI, treated with clopidogrel versus placebo; Table 2) (126). Furthermore, residual ADP-inducible platelet reactivity under dual antiplatelet therapy occurs more often in patients with CKD compared with patients with healthy kidney function, suggesting insufficient platelet inhibition (122,127,128). In contrast, a subgroup analysis of patients with CKD stage 3 (n=4849; GFR <60 ml/min per 1.73 m2) within the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial (RCT on patients with history of myocardial infarction, treated with ticagrelor versus placebo; Table 2) demonstrated that extended dual antiplatelet therapy with ticagrelor leads to a similar relative reduction, and even higher absolute reduction in ischemic risk compared with patients with a GFR >60 ml/min per 1.73 m2. This supports the therapeutic potential of antiplatelet therapy in these patients, although at the expense of increased minor bleedings (129).
Table 2. -
Clinical trials of P2Y
12 inhibitors and their effect on cardiovascular and bleeding risk in patients with chronic kidney disease with acute coronary syndrome or undergoing percutaneous coronary intervention
| Study |
Drug |
Study Type |
Patient Inclusion |
Cardiovascular Risk |
Bleeding Risk |
Reference |
| Hazard Ratio, Relative Risk, or Incidence (%) |
Relative Risk or Incidence (%) |
|
Cardiovascular and bleeding risk in patients treated with P2Y12 inhibitors in relation to kidney function
|
ADAPT-DES
(2015, post hoc analysis) |
Clopidogrel |
Observational, prospective study |
8582 patients undergoing PCI with drug-eluting stents and DAPT |
Incidence (%) of cardiac death, MI, or stent thrombosis:
CrCl >60: 6%
CrCl <60: 11% |
Incidence (%):
CrCl >60: 8%
CrCl <60: 14% |
(122) |
TRILOGY-ACS
(2016, post hoc analysis) |
Prasugrel or clopidogrel |
RCT |
8953 patients with ACS classified on the basis of CrCl:
Severe CKD: CrCl <30
Moderate CKD: CrCl 30–60
Normal kidney function/mild CKD: CrCl >60 |
Adjusted HR of CV death, MI, or stroke:
Severe versus normal/mild CKD: 1.60 (1.25 to 2.04)
Moderate versus normal/mild CKD: 1.26 (1.09 to 1.46) |
Adjusted HR of major bleeding:
Severe versus normal/mild CKD: 3.12 (1.32 to 7.34)
Moderate versus normal/mild CKD:
1.57 (0.94 to 2.63) |
(93) |
PLATO
(2010, post hoc analysis) |
Ticagrelor or clopidogrel |
RCT |
15,202 patients with ACS randomly assigned to ticagrelor or clopidogrel treatment and stratified according to kidney function, CKD: CrCl <60 (n=3237) |
CKD versus non-CKD:
HR of CV death, MI, or stroke: 1.12 (1.11 to 1.13); of CV death: 1.19 (1.17 to 1.21); MI: 1.08 (1.07 to 1.10); and stroke: 1.11 (1.08 to 1.15) for every decrease in CrCl of 5 ml/min per 1.73 m2
|
CKD versus non-CKD:
HR of major bleeding: 1.04 (1.03 to 1.05) for every decrease in CrCl of 5 ml/min per 1.73 m2
|
(123) |
PROMETHEUS
(2017, post hoc analysis) |
Prasugrel or clopidogrel |
Observational |
19,832 patients with ACS undergoing PCI;
CKD (eGFR <60; 28%) |
CKD versus non-CKD:
HR of major adverse cardiac event: 1.27 (1.18 to 1.37); of CV death: 1.59 (1.37 to 1.85); and MI: 1.36 (1.17 to 1.58) |
CKD versus non-CKD:
HR of bleeding: 1.46 (1.24 to 1.73) |
(94) |
SWEDEHEART
(2017) |
Clopidogrel
(>3 versus 3 months) |
Observational, prospective study |
36,001 patients with ACS, classified on the basis of eGFR:
eGFR >60 (n=28,653)
eGFR 45–60 (n=4387)
eGFR 30–45 (n=2127)
eGFR <30 (n=834) |
HR of death, MI, or stroke (longer versus 3-month treatment):
eGFR >60: 0.76 (0.67 to 0.85)
eGFR 45–60: 0.85 (0.70 to 1.05)
eGFR 30–45: 0.78 (0.62 to 0.97)
eGFR <30: 0.93 (0.70 to 1.24) |
Bleeding more common on longer versus 3-month treatment in each CKD stratum |
(124) |
|
|
|
The proportion of registered deaths, MI, strokes increased with worse kidney function in both DAPT groups |
The calculated bleeding incidence was higher in worse CKD strata |
|
Effect of clopidogrel or ticagrelor ( versus placebo) on cardiovascular and bleeding risk in relation to kidney function
|
CURE
(2007, post hoc analysis) |
Clopidogrel versus placebo |
RCT |
12,253 patients with ACS grouped into tertiles of GFR:
Upper tertile: >81.3 (n=4091)
Medium tertile: 64.0–81.2 (n=4075)
Lower tertile: <64.0 (n=4087) |
RR of CV death, MI, or stroke (clopidogrel versus placebo):
Upper tertile: 0.74 (0.60 to 0.93)
Medium tertile: 0.68 (0.56 to 0.84)
Lower tertile: 0.89 (0.76 to 1.05) |
RR of major bleeding (clopidogrel versus placebo):
Upper tertile: 1.83 (1.23 to 2.73)
Medium tertile: 1.40 (0.97 to 2.02)
Lower tertile: 1.12 (0.83 to 1.51) |
(125) |
|
|
|
Clopidogrel reduces cardiovascular risk also in mild CKD |
|
|
CREDO
(2008, post hoc analysis) |
Clopidogrel versus placebo |
RCT |
2002 patients undergoing PCI, categorized by estimated CrCl:
normal: >90 (n=999), mild: 60–89 (n=672), moderate: <60 (n=331) |
Incidence (%) of death, MI, or stroke after 1 year (clopidogrel versus placebo):
Normal: 4% versus 10%, P<0.001
Mild: 10% versus 13%, P=0.30
Moderate: 18% versus 13% P=0.24 |
RR of major or minor bleeding (clopidogrel versus placebo):
Normal: 1.235 (1.010 to 1.511)
Mild: 1.310 (1.058 to 1.622)
Moderate: 1.081 (0.822 to 1.420) |
(126) |
|
|
|
Clopidogrel smaller beneficial effect on cardiovascular risk in CKD compared with non-CKD |
Clopidogrel increases risk of bleeding across all groups |
PEGASUS-TIMI 54
(2016, post hoc analysis) |
Ticagrelor versus placebo (extended treatment duration) |
RCT |
20,898 patients with history of MI, and stratified on the basis of kidney function
eGFR <60, n=4849 |
RR of CV death, MI, or stroke (ticagrelor [60 and 90 mg twice daily] versus placebo):
eGFR <60: HR: 0.81 (0.68 to 0.96)
eGFR ≥60: HR: 0.88 (0.77 to 1.00) |
Bleeding risk upon ticagrelor treatment (60 and 90 mg twice daily) in patients with eGFR<60 versus ≥60:
Major bleeding: 1.19% versus 1.43%
Minor bleeding: 1.93% versus 0.69% |
(129) |
|
|
|
Reduction in relative risk in MACE on ticagrelor is similar; absolute risk reduction in MACE on ticagrelor is greater in the eGFR <60 group |
Increase in major bleeding on ticagrelor: similar in CKD compared with non-CKD, increase in minor bleeding on ticagrelor more pronounced in the eGFR <60 group |
|
Comparison of prasugrel or ticagrelor with clopidogrel on cardiovascular and bleeding risk in patients with CKD
|
TRITON-TIMI 38
(2007, post hoc analysis) |
Prasugrel versus clopidogrel |
RCT |
13,380 patients with moderate-to-high–risk ACS with scheduled PCI:
CrCl <60 (n=1490) |
Incidence (%) of:
death from CV causes, nonfatal MI, or nonfatal stroke (prasugrel versus clopidogrel):
CrCl <60: 15.1% versus 17.5%
CrCl ≥60: 9.0% versus 11.1% |
— |
(130) |
|
|
|
Prasugrel does not significantly reduce cardiovascular risk in comparison to clopidogrel in patients with ACS with CrCl <60 |
|
|
TRILOGY-ACS
(2012, post hoc analysis) |
Prasugrel versus clopidogrel |
RCT |
7243 patients with unstable angina or NSTEMI who do not undergo revascularization;
CrCl >60 (n=5432)
CrCl 30–60 (n=1407)
CrCl <30 (n=105) |
HR for composite death from CV causes, nonfatal MI, or nonfatal stroke (prasugrel versus clopidogrel):
CrCl >60: HR: 0.88 (0.73 to 1.05)
CrCl 30–60: HR: 1.14 (0.88 to 1.49)
CrCl <30: HR: 0.68 (0.33 to 1.41) |
HR for non-CABG–related TIMI major bleeding (prasugrel versus clopidogrel):
CrCl >60: HR: 1.58 (0.89 to 2.80)
CrCl 30–60: HR: 0.71 (0.25 to 2.00)
CrCl <30: HR: 0.46 (0.04 to 2.10) |
(131) |
|
|
|
Prasugrel does not significantly reduce cardiovascular risk in comparison to clopidogrel |
|
|
PROMETHEUS
(2017, post hoc analysis) |
Prasugrel versus clopidogrel |
Observational |
19,832 patients with ACS undergoing PCI;
CKD (eGFR <60; 28.3%) |
In patients with ACS with CKD: HR for (prasugrel versus clopidogrel):
CV death: HR: 0.93 (0.50 to 1.73),
MI: HR: 1.10 (0.66 to 1.87)
Unplanned revascularization: HR: 1.17 (0.72 to 1.89)
Stent thrombosis: HR: 0.50 (0.06 to 4.29) |
Bleeding: HR: 1.06 (0.66 to 1.72) |
(94) |
|
|
|
No benefit from prasugrel over clopidogrel in terms of cardiovascular risk |
No benefit from prasugrel over clopidogrel in terms of bleeding risk |
PLATO
(2010, post hoc analysis) |
Ticagrelor versus clopidogrel |
RCT |
15,202 patients with ACS randomly assigned to ticagrelor or clopidogrel treatment and stratified according to kidney function, CKD: CrCl <60 (n=3237) |
Incidence (%) of CV death, MI, and stroke in CKD subgroup (ticagrelor versus clopidogrel):
17.3% versus 22.0%, HR: 0.77 (0.65 to 0.90)
Mortality: 10.0% versus 14.0%, HR: 0.72 (0.58 to 0.89) |
In CKD subgroup (ticagrelor versus clopidogrel):
Major bleeding: 15.1 versus 14.3%, HR: 1.07 (0.88 to 1.30)
Fatal bleeding: 0.34 versus 0.77, HR: 0.48 (0.15 to 1.54)
Non-CABG major bleeding: 8.5% versus 7.3%, HR: 1.28 (0.97 to 1.68) |
(123) |
|
|
|
Ticagrelor reduces cardiovascular risk over clopidogrel |
Ticagrelor no significant effect on bleeding over clopidogrel |
| Mavrakanas T. et al. 2021 |
Prasugrel versus clopidogrel
Ticagrelor versus clopidogrel |
Observational, retrospective study |
7718 patients with CKD on hemodialysis or peritoneal dialysis treated with:
clopidogrel: 6648
prasugrel: 621
ticagrelor: 449 |
In patients with CKD5D who had a drug-eluting stent implanted, HR for primary outcome (CV death, MI, and stroke):
prasugrel versus clopidogrel:
0.96 (0.82 to 1.11)
ticagrelor versus clopidogrel:
1.00 (0.83 to 1.20) |
Clinically relevant bleeding, HR:
prasugrel versus clopidogrel:
1.15 (0.95 to 1.38)
ticagrelor versus clopidogrel
1.13 (0.91 to 1.40) |
(133) |
95% confidence intervals are indicated in parentheses. All patients received acetylsalicylic acid concomitantly. PCI, percutaneous coronary intervention; DAPT, dual antiplatelet therapy; MI, myocardial infarction; CrCl, creatinine clearance; RCT, randomized controlled trial; HR, hazard ratio; CV, cardiovascular; ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CHD, coronary heart disease; HF, heart failure; RR, relative risk; MACE, major adverse cardiovascular event; NSTEMI, non-ST segment elevation myocardial infarction; CKD5D, stage 5D CKD.
Comparison of Different P2Y12 Inhibitors
Given that prasugrel and ticagrelor are more potent P2Y12 inhibitors than clopidogrel, there is an ongoing debate on which P2Y12 inhibitor to administer to best balance thrombotic versus bleeding risk. When comparing prasugrel to clopidogrel in small subgroup analyses of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) trial (patients with moderate-to-high–risk ACS with scheduled PCI), Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY-ACS) trial (including patients with ACS either invasively or medically managed), and the PROMETHEUS registry (patients with ACS undergoing PCI), a trend was observed toward more favorable effects of prasugrel over clopidogrel in terms of cardiovascular risk reduction in patients with ACS with CKD stage 3 and beyond, although statistically no benefit could be revealed with prasugrel (Table 2) (94,130,131). For ticagrelor versus clopidogrel, the Platelet Inhibition and Patient Outcomes (PLATO) trial (RCT, patients with ACS) revealed that patients with CKD stage 3 and beyond benefit from ticagrelor, compared with clopidogrel, with a significant risk reduction for cardiovascular death, myocardial infarction, or stroke (Table 2) (123). However, the effect of prasugrel and ticagrelor in the context of CKD needs further clarification by sufficiently powered trials. Furthermore, data on direct comparison of prasugrel and ticagrelor remain scarce, with first insights coming from the recently published Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 (ISAR-REACT 5) trial that compared ticagrelor to prasugrel treatment in patients with ACS. In an underpowered subgroup analysis (prasugrel n=88 patients, ticagrelor n=125 patients), prasugrel was superior to ticagrelor in patients with a creatinine of higher than 1 mg/dl (eGFR not provided by the authors), which might correspond to very mild CKD (stage 1–2) (132). Finally, a comparison of the effect of different P2Y12 inhibitors on cardiovascular and bleeding risk in patients on dialysis remains scarce. Recently, a retrospective study of the United States Renal Data System data concluded that specifically for patients with kidney failure (CKD5D) after implantation of drug-eluting stents, prasugrel or ticagrelor do not offer a significant benefit over clopidogrel in terms of cardiovascular outcome, whereas they are associated with a trend toward a higher bleeding risk (Table 2) (133).
Summary
In summary, as apparent from predominantly post hoc subgroup analyses of dual antiplatelet therapy, P2Y12 inhibitors can reduce the risk on recurrent cardiovascular events after stent implantation in patients with CKD not on dialysis, although with potentially reduced efficacy compared with the general population and with increasing bleeding risk (Figure 2B). However, patients with CKD, in particular those with stage ≥CKD4, are often underrepresented or even excluded from major clinical trials that assess antiplatelet therapies (Figure 3). Sufficiently powered trials, in particular for patients with CKD stage 4 and beyond, are needed to further guide therapy in daily practice in patients who are high risk (116,134). The Ticagrelor or Clopidogrel in Severe and Terminal Chronic Kidney Disease Patients Undergoing Percutaneous Coronary Intervention for an Acute Coronary Syndrome (TROUPER) trial is recruiting patients with ACS with CKD stage 3b and beyond to compare the efficacy and safety of ticagrelor versus clopidogrel in reducing major adverse cardiovascular events (death, myocardial infarction, urgent revascularization, and stroke) and bleeding, respectively, and as such determine the optimal antiplatelet strategy for this patient population (NCT03357874) (135).
Risk/Benefit Balance of Antiplatelet Therapies in CKD
In the case of antiplatelet therapies, it needs to be considered that patients with CKD are not only prone to atherothrombotic events but also to bleeding. Accordingly, the 2012 Kidney Disease Improving Global Outcomes guidelines recommend offering antiplatelet agents to adult patients with CKD unless the risk of bleeding outweighs the possible cardiovascular benefits (136). In addition, bleeding may affect guideline-oriented antiplatelet therapy. For example, in the Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study (patients with ACS treated with PCI), increased moderate to severe bleeding in patients with CKD led to significantly more interruptions in the administration of P2Y12 inhibitors and potentially exposed these patients to a higher atherothrombotic risk (137). In addition, a subgroup analysis from the PROMETHEUS registry (patients with ACS undergoing PCI) demonstrated that patients with CKD stage 3 and beyond were 50% less likely to receive prasugrel despite their higher atherothrombotic risk, suggesting a potential undertreatment of cardiovascular risk (94). More insight into the bleeding risk of the individual patient may aid clinicians in selecting the best treatment strategy for their patient (138–140). However, as current bleeding scores in which identified risk factors for bleeding are included were shown to be suboptimal in patients on dialysis, new dialysis/CKD-specific scores are recommended (141).
Perspectives
CKD associates with contrasting abnormalities in platelet function, which can be linked to the observed increase in both thrombotic and hemorrhagic complications. Antiplatelet therapy can reduce thrombotic risk in CKD but comes at the expense of impaired hemostasis. This brings a careful consideration of benefits versus risks of antiplatelet therapy in these patients. Furthermore, despite antiplatelet therapy, patients with CKD remain at higher cardiovascular risk compared with patients without CKD on antiplatelet therapy. Current experience with antiplatelet therapy in CKD is predominantly on the basis of underpowered post hoc analyses of large registries in which patients with stage ≥CKD4 are often underrepresented or even excluded. Sufficiently powered trials, in particular for patients with CKD stage 4 and beyond, could help to better guide therapy in daily practice in these patients who are high risk. This would also provide further insights into whether thrombotic risk reduction by antiplatelet therapy may be CKD-stage dependent, with potentially smaller benefits in more progressed CKD (134). Furthermore, apparently conflicting findings are reported on platelet activity in CKD and on response to antiplatelet therapy. Whether this can be explained by heterogeneity in underlying pathologies, comorbidities, or CKD disease severity itself needs to be further investigated. Moreover, classification of CKD on the basis of eGFR, whose accuracy has been critically debated recently (142), might oversimplify disease severity and, as such, obscure relations between CKD severity on the one hand and platelet function and response to antiplatelet therapy on the other. A better understanding of the etiology underlying platelet dysfunction in relation to CKD progression may contribute to the optimization and development of current, respectively, novel antiplatelet treatment strategies, specifically tailored to patients with CKD.
Disclosures
J. Floege reports consultancy agreements with Amgen, Bayer, Calliditas, Novo Nordisk, Omeros, Travere, Vifor, and Visterra; reports receiving honoraria from Amgen, Astellas, Bayer, Calliditas, Novo Nordisk, Omeros, Travere, Vifor, and Visterra; reports serving as a scientific advisor or member of Calliditas, Omeros, and Travere; and reports speakers bureau for Amgen and Vifor. N. Marx reports consultancy agreements with AstraZeneca, Bayer, Boehringer Ingelheim, Genfit, Merck Sharp & Dohme Corp., and NovoNordisk; reports receiving research funding from Boehringer Ingelheim; reports receiving honoraria (reg. consultancy/speaking) to University Hospital Aachen (no personal honoraria); and reports speakers bureau for AstraZeneca, Bayer, Boehringer Ingelheim, and NovoNordisk. All remaining authors have nothing to disclose.
Funding
This work was supported by the Alexander von Humboldt Foundation (to C. Baaten), the Dutch Heart Foundation (2020T020, to C. Baaten), the START-Program of the Faculty of Medicine of the RWTH Aachen University (105/20 to C. Baaten and H. Noels), and by the German Research Foundation Project-ID 322900939, SFB/TRR219 (S-03, C-01, C-04, M-03, M-05 to J. Jankowski, H. Noels, J. Floege, and N. Marx) and Project-ID 403224013– SFB 1382 (A-04 to J. Jankowski and H. Noels). Further funding was provided by the CORONA foundation (to J. Jankowski and N. Marx) and the Else Kröner-Fresenius-Stiftung (Project 2020_EKEA.60 to H. Noels).
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