Table 2.
Clinical trials of P2Y12 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.