Academic Editor: Carlo Briguori
Background: Coronary artery disease (CAD) and chronic kidney disease (CKD) may reciprocally influence each other. Patients with CAD and CKD have an increased risk of both ischemic and hemorrhagic events. Methods: In the present review, we summarize the existing literature focusing on the relationship between kidney dysfunction and acute coronary syndromes (ACS) in terms of risk factors, complications, and prognosis. We discuss also about the best evidence-based strategies to prevent deterioration of renal function in patients with CAD. Results: Patients with CKD less frequently receive an invasive management (percutaneous or surgical revascularization) and potent antithrombotic drugs. Nevertheless, recent evidence suggests they would benefit from a selective invasive management, especially in case of ACS. Conclusion: Patients with CKD and CAD represent a challenging population, more randomized controlled trials and meta-analyses are needed to better define the best therapeutic strategy during an ACS episode.
The prevalence of chronic kidney disease (CKD) in the general population stands at 13% and increases to 20–25% in patients with acute coronary syndrome (ACS) [1]. CKD is an independent risk factor for cardiovascular events often consisting in pauci-symptomatic clinical presentation and atypical elettrocardiogram (ECG) changes, making the diagnosis of ACS more challenging.
It has been observed that as renal function decreases, cardiovascular risk progressively increases. Indeed, patients with renal dysfunction are most likely to present an acute myocardial infarction (AMI) [2] with an even higher prevalence of ACS in dialyzed patients. Indeed, chronic inflammation, hyperhomocysteinemia and oxidative stress leading to endothelial dysfunction, coronary artery calcification, as well as the use of immunosuppressants have all been associated with accelerated atherosclerosis and coronary events [3]. Periodic exposure of blood to the dialysis membrane may also induce platelet reactivity (PR), which leads to an increased risk of ischemic events and resistance to anti-thrombotic treatment in dialyzed patients [4, 5].
According to the Acute Kidney Injury (AKI) Network, AKI is defined as an absolute increase in serum creatinine (sCr) of 0.3 mg/dL or greater, or as an increase to 1.5-fold or greater from baseline. This definition was adopted by the universal guidelines developed by the KDIGO (Kidney disease–Improving global outcome) organization and is currently the most frequently used for any cause of acute renal injury [5].
A further definition has been proposed in the context of AKI relating to
contrast media used during percutaneous coronary intervention (PCI). It is based
on absolute increase in sCr level of at least 0.5 mg/dL (44 microMol/L) within
48–72 hours after contrast exposure or as a relative increase in sCr of
Several factors, such as parenchymal ischemia, direct and indirect tubular or endothelial damage, contribute to the development of contrast induced-AKI [7]. Contrast medium (CM) induces an increase in viscosity in the renal tubule leading to renal hypoperfusion through the constriction of the vasa recta [8]. Specifically, the CM-induced hypoxic damage afflicts both medullary and cortical regions, with a consequent reduction of estimated glomerular filtration rate (eGFR) and a concomitant tubular damage. The increase of reactive oxygen species and the reduction of nitric oxide leads to renal vasoconstriction ultimately resulting in additional tubular as well as endothelial damage. This effect varies according to the osmolarity and the viscosity of the CM, with maximum damage produced by high osmolarity iodine-based contrast agent (HOCM). Furthermore, HOCM influences the shape of the erythrocytes, causing difficulties in the passage inside the vasa recta with consequent hypoxia of the medullary region [8, 9, 10, 11].
The most important risk factor associated with contrast induced-AKI is a
pre-existing renal dysfunction [5]. The risk of contrast induced-AKI becomes
clinically evident when the baseline sCr concentration is
Fundamental strategies to prevent and treat contrast induced-AKI are directed to restore circulatory volume. High osmolarity of CM and increased viscosity may be mitigated with adequate hydration to reduce the CM concentration. To date several hydration strategies have been developed. In the POSEIDON trial, a left ventricular end diastolic pressure guided fluid administration resulting in a significant reduction of contrast induced-AKI compared to usual care [15]. Another strategy is based on the use of the RenalGuard® System in which the losses due to an infusion of furosemide (0.25 mg/kg) are counterbalance by an equivalent intravenous infusion of saline solution. In the REMEDIAL II trial, the use of the RenalGuard® System led to a reduction of the incidence of contrast induced-AKI [16].
The European guidelines recommend using pre-procedure infusion of isotonic
solution starting 12 hours before the angiography, and continuing for at least 24
hours afterwards, in order to reduce the risk of contrast induced-AKI, especially
if eGFR is
Although the use of adequate hydration remains the cornerstone for prevention of
the development of contrast induced-AKI, great attention has been placed on
trying to minimize the volume of the CM. In this regard, several strategies have
been developed, including the use of automatic systems for the injection of the
contrast medium, such as: ACIST CVi® (ACIST Medical Systems, Eden
Prairie, MN, USA), MEDRAD® Avanta system (MEDRAD Inc.,
Warrendale, PA, USA) and the AVERT™ system, followed by the
second-generation DyeVert™ systems (Osprey Medical, Minnetonka,
MN, USA). In the AVERT trial, AVERT™ system, in spite of having
demonstrated a decrease in the volume of CM compared to traditional methods,
failed to accomplish a reduction in the incidence of contrast induced nephropaty
(CIN), suggesting that the obtained reduction in the volume of CM that had been
obtained was not sufficient to reduce the incidence of AKI [24]. The
DyeVert™ system has been recently assesed in a retrospective
analysis [25] of 112 patients with ACS undergoing primary PCI: use DyeVert
resulted in lower contrast media used (130 [120–188] mL vs. 99 [69–136] mL;
p
Several studies have focused their attention on PCI not guided by angiographies
[26]. One of these, the MOZART trial, shows how ultrasound-guided PCI is
effective in reducing the requirement of CM. In another study a total of 31
patients with advance CKD (eGFR
Approximately 25% to 30% of all ACS patients presents at least moderately reduced renal function [30, 31]. Noninvasive estimation of renal function is mandatory in every patient with confirmed or suspected ACS admitted to the hospital [32]. Reduced renal function and CKD affect every stage of diagnostic and therapeutic pathway of ACS, with an important prognostic relevance.
High-sensitivity cardiac troponins (hs-cTn) are the best available biomarkers
for early diagnostic of ACS but in CKD patients they are chronically elevated,
limiting their clinical usefulness [31, 33]. In a retrospective study, 3295
patients presenting chest pain were classified in subgroups based on age, sex and
renal function. AMI was diagnosed in 84% of the patients and hs-cTn levels were
compared between AMI and non-AMI patients in all subgroups. Optimal cut-offs
values of high-sensitivity cardiac troponin I (hscTnI) for diagnosis of AMI in
CKD (eGFR
CKD may worsen the short and long-term prognosis of patients admitted for ACS
(Fig. 1). Patients with moderate and severe CKD showed significantly increased
risk of hospitalization, mortality and major bleeding episodes (Table 1, Ref. [2, 30, 36, 37, 38, 39, 40, 41, 42]). In the HORIZONS-AMI study, patients with CKD and
ST-segment elevation myocardial infarction (STEMI) treated with PCI showed higher
risk of mortality, stroke, mayor adverse cardiac events (MACE), and net adverse
clinical events (NACE) and non-coronary artery bypass surgery (CABG) related
bleeding at 3 years, compared with patients without CKD. Notably, the mortality
rate in patients with advanced CKD (creatinine clearance [Crcl]
Kidney dysfunction and acute coronary syndrome.
Authors | n | Aims and groups | Primary endpoint | Secondary endpoints |
Go et al. [2], 2004 | 1,120,295 | Correlation between the GFR and risks of death, CV events, and hospitalization. | HR for death: 1.2 (95% CI 1.1–1.2), 1.8 (95% CI 1.7–1.9), 3.2 (95% CI 3.1–3.4), and 5.9 (95% CI 5.4–6.5), inversely related to GFR. | HR for Any Hospitalization: 1.1 (95% CI 1.1–1.1), 1.5 (95% CI 1.5–1.5), 2.1 (95% CI 2.0–2.2), and 3.1 (95% CI 3.0–3.3), respectively. |
Results related to group of eGFR (45–59, 30–44, 15–29, and |
HR for MACE: 1.4 (95% CI 1.4–1.5), 2.0 (95% CI 1.9–2.1), 2.8 (95% CI 2.6–2.9), and 3.4 (95% CI 3.1–3.8), respectively. | |||
Fox et al. [30], 2012 | 59,970 (100% with ACS) | To examine in-hospital all cause death and major bleeding in patients with AKI in setting of MI. | In-hospital all-cause death. | Crude rates of major bleeding: mild AKI 16.5%, moderate AKI 22.6% and severe AKI 32.7%. |
Classification as absolute change in sCr: mild (sCr 0.3–0.5 mg/dL), moderate (SCr 0.5–1.0), and severe AKI (SCr |
OR: 2.4 (95% CI 2.0–2.7) for mild AKI; 4.5 (95% CI 3.9–5.1) for moderate AKI; 12.6 (95% CI 11.1–14.3) for severe AKI. | |||
De Rosa et al. [36], 2020 | 1904 (100% with ACS) | Correlation between contrast induced-AKI and adverse one-year outcome in elderly patients (mean age 81.0 |
Risk of all-cause mortality at 12 months: 4.5%, 7.5% and 17.8% inversely related to GFR (p |
Severe contrast induced-AKI is associated with a higher risk of all-cause (HR 2.86, 95% CI 1.52–5.37, p = 0.001) and CV death (HR 3.11, 95% CI 1.41–6.83, p = 0.005). |
Risk of CV mortality at 12 months: (2.8%, 5.2% and 10.2%, respectively). | Contrast induced-AKI incidence significantly higher in STEMI vs. NSTEMI (11.7% vs. 7.8%, p = 0.036). | |||
Charytan et al. [37], 2006 | 154,692 (100% with ACS) | To indagate use of coronary angiography (CA) and PCI in patients with CKD (n = 8957) dialysis (n = 2369). | Rate of CABG or PCI was 19.2% in dialyzed patients, 23.0% in patients with CKD, and 41.4% in control group (RR 0.46 [95% CI 0.42–0.52] and 0.56 [95% CI 0.53–0.59] respectively). | Rate of CABG or PCI after CA was 46.4% (RR 0.66, 95% CI 0.61–0.72) in dialysis patients, 61.6% (RR 0.88, 95% CI 0.86–0.90) in patients with CKD, and 70.1% in control group. |
Rates of diagnostic CA were 38.6% in dialyzed patients (RR 0.68, 95% CI 0.64–0.73), 34% in patients with CKD (RR 0.62, 95% CI 0.59–0.64) than in control (56.6%). | ||||
Szummer et al. [38], 2009 | 23,262 patients (100% with NST-ACS) | To investigate 1 year outcome after early invasive management in NSTEMI patients with CKD. | No benefit for PCI in advanced CKD (eGFR |
Rate of patients treated invasively with declining renal function: from 62% with eGFR |
Holzmann et al. [39], 2020 | 12,821 patients (100% with NST-ACS) | Benefit of PCI in NSTEMI for elderly patients (mean age 86 years old) with CKD. | Absolute risk of death was 42%, 56%, and 76%, respectively. | OR for in hospital re-IMA: 1.76 (0.71–4.37), 1.89 (0.95–3.76), 3.03 (0.90–10.22), respectively. |
Stratification related to eGFR: |
HR death risk after PCI was lower all groups: 0.47 [95% CI 0.42–0.53], 0.50 [95% CI 0.45–0.56], and 0.44 [95% CI 0.33–0.59], respectively. | OR for in hospital bleeding: 1.62 (0.86–3.08), 1.22 (0.73–2.03), 2.77 (1.03–7.49). | ||
James et al. [40], 2010 | 15,202 (100% with ACS) | Efficacy and safety of ticagrelor vs. clopidogrel in relation to renal function. | In patients with CKD, ticagrelor vs clopidogrel reduced the composite endpoint (CV death, MI and stroke) from 22.0% to 17.3% (HR, 0.77; 95% CI 0.65 to 0.90). | Major bleeding rates, not different (15.1% vs. 14.3%; HR, 1.07; 95% CI 0.88–1.30). |
De Filippo et al. [41], 2020 | 19,255 (100% with ACS) | Safety and efficacy profile of prasugrel and ticagrelor in real-life ACS patients with CKD. | Prasugrel and ticagrelor reduced the mortality rate (HR 0.82, 95% CI 0.54–0.96; p = 0.006) and the risk of reinfarction (HR 0.53, 95% CI 0.30–0.95; p = 0.033) in CKD patients as compared to clopidogrel. | DAPT with either ticagrelor or prasugrel did not result in an increased risk of major bleedings in CKD patients (HR 1.00, 95% CI 0.59–1.68; p = 0.985). |
Valle McCoy et al. [42], 2017 | 453,475 (66.95% with ACS) | Contrast induced-AKI after PCI, risk and prognosis. | Rate of Contrast induced-AKI was 8.8%. | Re-Hosp for AKI: AKIN 1, HR 1.70 (95% CI 1.64–1.76); AKIN 2/3: HR 2.22 (95% CI 2.04–2.41). |
AKIN stages: | Primary outcome (death, MI, or bleeding within 1 year of hospital discharge): | Dialysis: AKIN 1 HR, 2.59 (95% CI 2.29–2.92); AKIN 2/3 HR, 4.73 (95% CI 3.73–5.99). | ||
1. as a |
AKIN 1: HR 1.53; (95% CI 1.49–1.56). | MI: AKIN stage 2/3: HR, 1.29 (95% CI 1.15–1.45); AKIN stage 1 HR 1.32 ( 95% CI 1.26–1.38). | ||
2. as a |
AKIN 2/3: HR 2.13; (95% CI 2.01–2.26). | Bleeding: AKIN stage 2/3: HR, 1.40; 95% CI 1.19–1.66; AKIN stage 1: HR, 1.31; 95% CI 1.23–1.40). | ||
3. as a sCr creatinine |
Patients with CKD have been frequently excluded from ACS trials [37]. While the
decision-making for patients admitted with ACS ST-elevation requires invasive
revascularization when feasible, managing patients with ACS without persistent
ST-elevation with CKD is challenging for a lack of evidence. In a retrospective
analysis from SWEDEHEART data, the incidence of coronary revascularization and
its effect on mortality were evaluated in 23,262 ACS patients aged
A more recent retrospective study from the SWEDEHEART registry included ACS
patients
A meta-analysis of comparative studies carried out between 1995 and 2010
analysing the effect of early revascularization in patients with NSTEMI and CKD,
showed interesting benefits from early revascularization on short- and long-term
mortality. Specifically, a reduction in 1-year mortality compared to initial
medical therapy (OR = 0.46, 95% CI 0.26–0.82, p = 0.008) among ACS
patients with eGFR
The Academic Research Consortium for High Bleeding Risk (ARC-HBR) recognizes
severe or end-stage CKD (eGFR
DAPT is highly recommended in ACS patients to improve outcome and prognosis, regardless of renal function. However, the efficacy and safety of antithrombotic drugs with potent P2Y12 inhibitors, a chemoreceptor for platelets released adenosine diphosphate (ADP), in patients with severe CKD or ESRD are not clearly evaluated, since these patients are frequently excluded from randomized controlled trials [46]. In patient with ACS and CKD there are no contraindications for aspirin, no dose adjustment is required if renal function is reduced [47, 48]. Clopidogrel is a prodrug and need activation to bind the ADP receptor. Standard dose of clopidogrel has a lower inhibition of ADP-induced platelet aggregation (–25%) in patients with depressed renal function, and is associated with greater prevalence of high on-treatment platelet reactivity (HTPR), leading to an increased ischemic risk [49, 50]. In the ARTIC study, 2440 patients were randomized before drug-eluting stent implantation, both using a strategy of platelet function monitoring and without monitoring. In the monitoring group, 35% of patients had high platelet reactivity (HPR) to clopidogrel [51]. Patients with CKD have a higher risk of HTPR, with an increased rate in lower renal function groups. However, after multivariable adjustment, no significant association was detected between HTPR and CKD, suggesting that risk factors account for HPR in patients with renal impairment [52]. Post hoc analyses of CREDO trial (Clopidogrel for the Reduction of Events During Observation) show a limited efficacy, defined as death, myocardial infarction or stroke, and higher risk of bleeding, after 1 year of clopidogrel vs. placebo in patients with mild to moderate CKD [52]. Similar findings were observed in other analyses [53, 54]. Several studies show the superiority of potent oral P2Y12-ADP receptor antagonists, ticagrelor and prasugrel, over clopidogrel in CKD patients [55, 56, 57, 58]. Despite the clinical benefits of potent P2Y12-ADP receptor antagonists over clopidogrel in patients with ACS [59, 60], clinical and therapeutic experience with prasugrel and ticagrelor is limited in patients with renal impairment (including patients with ESRD).
In the subgroup analysis of the TRITON TIMI 38 trial, including 1490 patients
with a eGFR
In a multicenter, retrospective, observational study from BleeMACS and RENAMI
the benefits and safety of potent P2Y12 inhibitors in CKD and ACS patients were
investigated. In 19,255 CKD patients (12.9% with eGFR
In recent years, the attention has been focused on intravenous antiplatelet
drugs, which offer a reduction of ischemic events in patients with ACS undergoing
PCI. These drugs play a central role extending from perioperative bridging to
planned surgery that requires stop of oral P2Y12 antagonist. Two classes of drugs
can be defined: glycoprotein IIb/IIIa inhibitors (GPIs) (abciximab, tirofiban,
and eptifibatide) and Cangrelor. GPIs block glycoprotein IIb/IIIa receptors on
platelet’s plasma membrane, preventing the binding of fibrinogen and thus
platelet aggregation [31]. Tirofiban and Eptifibatide are renally eliminated and
need dosage adjustment if used in patients with CKD. Explicit contraindications
exist when used in patients with eGFR less than 15 mL/min/1.73 m
When administered within the first 24 hours, angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are fundamental compounds of post-MI therapy for reducing fatal and nonfatal MACE [61, 65]. Nevertheless, evidence is less robust in CKD patients, since there is not a clear cut-off level of sCr that contraindicates the use of these agents [65]. Both ESC and American Heart Association (AHA) STEMI guidelines, state that renal dysfunction should be taken into account as a contraindication for their routine use of ACE-I or ARB [66, 67, 68, 69, 70, 71].
There is a paucity of evidence about the use of Sacubitril/Valsartan in patients
with CKD and ACS. A recent randomized trial, PARADISE-MI, did not find any
statistical significance in MACE rate with the initiation of sacubitril/valsartan
therapy vs ramipril in patients with a high risk of heart failure surviving an
ACS, regardless of moderate CKD presence (defined as eGFR
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) represent a new class of oral hypoglycemic agents used for the treatment of heart failure with reduced ejection fraction, regardless of the presence of DM. To date, evidence about the favorable outcome in CKD patients with ACS treated with SGLT2i is scarce. However, several studies have found a better renal outcome in DM patients with CKD treated with canagliflozin [73] and dapagliflozin [74]. An ongoing study is investigating the use of SGLT2i in DM patients with ACS (ClinicalTrials.gov Identifier: CT0503705; ClinicalTrials.gov Identifier: NCT05037058).
A high ischemic risk and rate of AMI occur in CKD patients, with an even higher prevalence in dialyzed patients. Both cardiac and kidney dysfunction may worsen the prognosis and lead to disease progression. Therapeutic strategies employed in ACS can expose CKD patients to higher rates of major and fatal bleeding. This condition leads to an undertreatment attitude and to a conservative approach for patients with renal impairment. Patients with CKD are less frequently treated with percutaneous or surgical revascularization even thought they could potentially benefit from a more invasive management. Moreover, the use of potent P2Y12-ADP antagonists could be considered a significant advantage for CKD patients. Further clinical studies are needed to assess the best treatment strategies for this high-risk subset of patients.
Systematic review of literature—LDL, VF, MDM. Drafting and final approval—LDL, RM and FAV.
Not applicable.
The authors thank to Alessandra Picariello, in quality of professional English language revisor, for her contribution to the linguistic revision of the manuscript.
This research received no external funding.
The authors declare no conflict of interest. Leonardo De Luca is serving as one of the Editorial Board members of this journal. We declare that Leonardo De Luca had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Carlo Briguori.