Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial

Optimal antithrombotic/anticoagulation therapy in patients on chronic oral anticoagulation (OAC) undergoing drug-eluting stent (DES) implantation is unknown. We investigated the efficacy and safety of two regimens of antithrombotic/anticoagulation therapy in patients who present for DES implantation whilst on OAC. We included a series of 515 patients on OAC who underwent DES implantation between 2002 and 2007. Based on predefined clinical and echocardiographic criteria, 306 patients continued OAC (triple therapy) and 209 patients discontinued OAC (dual therapy) for the time they received antiplatelet therapy with clopidogrel and aspirin [stent-related antithrombotic treatment (SRAT)]. The primary end point was a composite of death, myocardial infarction, stent thrombosis or stroke. During SRAT the primary endpoint was observed in 13 patients in the group with triple therapy versus 15 patients in the group with dual therapy [Kaplan-Meier estimates 4.2% and 7.2%, odds ratio (OR) = 0.61, 95% confidence interval (CI) 0.29-1.28; P = 0.19]. At 2 years of follow-up, the primary endpoint was observed in 35 patients in the group with triple therapy versus 36 patients in the group with dual therapy (Kaplan-Meier estimates 14.1% and 18.0%, OR = 0.76, 95% CI: 0.48-1.21; P = 0.25). Two-year incidence of major bleeding was 1.4% (n = 4, triple therapy) versus 3.1% (n = 6, dual therapy) (P = 0.34). In patients on chronic OAC undergoing DES implantation, clinical and echocardiographic criteria help to define postprocedural antithrombotic/anticoagulation therapy. Based on these criteria, both a double antiplatelet therapy (clopidogrel plus aspirin) and a triple therapy (OAC plus clopidogrel plus aspirin) are associated with favourable safety and efficacy.

Background: The optimal antithrombotic regimen for patients with coexistent atrial fibrillation (AF) and coronary artery disease (CAD) requiring percutaneous coronary intervention (PCI) remains controversial. Methods: We performed a chart review of 2,645 consecutive patients with non-ST elevation or ST elevation myocardial infarction at a regional cardiac centre, to examine the clinical characteristics and discharge antithrombotic medications of patients with coexistent AF (known or new onset AF with CHADS 2 ≥1), treated with PCI. Results: Among 2,645 patients, 94 eligible patients were analyzed and 30 (32%) were prescribed triple therapy (TT) at hospital discharge. CHADS 2 score was the major predictor of the decision to prescribe TT ( P=0.002). Conclusion: Approximately one-third of the patients with AF undergoing PCI were prescribed TT at hospital discharge. Clinicians are generally following national guidelines and internationally-developed consensus statements, and focus on stroke risk despite the risks of bleeding and insufficient evidence supporting the benefits of TT.

Case Presentation: A 76-year-old man was admitted with retrosternal chest pain. The ECG on admission showed inferolateral ST depression, and troponin levels were elevated, confirming the diagnosis of an acute coronary syndrome. The patient had a history of hypertension and aortic valve replacement with a metallic bileaflet valve 7 years before. He was being treated with warfarin and low-dose aspirin and had an international normalized ratio (INR) of 2.5. Coronary angiography revealed a long subocclusive lesion of the proximal right coronary artery. At that point, there was a question about the optimal treatment for this patient regarding the type of stent to be selected and the need for future combined antiplatelet and anticoagulation treatment. Oral anticoagulation was routinely used for coronary stent thrombosis prevention during the first era of stents.1 It has since been replaced by the combination of aspirin and a thienopyridine because studies have shown a definite advantage of the antiplatelet combination on coronary events2–4 and on reducing the risk of access-site bleeding complications. However, ≈5%5,6 of patients undergoing percutaneous coronary intervention (PCI) also present with an indication for oral anticoagulation therapy. In such cases, the type of stent selected; the use of oral anticoagulants, antiplatelets, or their combinations; the target INR; and the duration of treatment are essential considerations in relation to the risk of stent thrombosis/thromboembolic events and bleeding risk. With the introduction and widespread use of drug-eluting stents (DES) in recent years and given the necessity for longer duration of dual antiplatelet therapy, the issue of concurrent warfarin and antiplatelet therapy has become even more important. The existing guidelines do not offer a convincing solution to these issues. For acute coronary syndrome patients with an indication for anticoagulation, triple therapy (warfarin, aspirin, and clopidogrel) for the minimum time possible and a maintenance …

Antiplatelet therapy and anticoagulants

The type of periprocedural antithrombotic regimen that is the safest and most effective in percutaneous coronary intervention (PCI) patients on oral anticoagulant (OAC) therapy has not been fully investigated. We aimed to retrospectively investigate the in-hospital bleeding outcomes of patients receiving OAC and antiplatelet therapies during PCI using Japanese nationwide multicenter registry data. A total of 26,938 patients who underwent PCI with OAC and antiplatelet therapies between 2016 and 2017 were included. We investigated in-hospital bleeding requiring blood transfusion, mortality, and stent thrombosis according to the antithrombotic regimens used at the time of PCI: OAC + single antiplatelet therapy (double therapy) and OAC + dual antiplatelet therapy (triple therapy). The antiplatelet agents included aspirin, clopidogrel, and prasugrel. The OAC agents included warfarin and direct OACs. Adjusting the dose of OAC or intermitting OAC before PCI was at each operator's discretion. In the study population [mean age (SD), 73.5 (9.5) years; women, 21.5%], the double therapy and triple therapy groups comprised 5546 (20.6%) and 21,392 (79.4%) patients, respectively. Bleeding requiring transfusion was not significantly different between the groups [adjusted odds ratio (aOR), 0.700; 95% confidence interval (CI), 0.420-1.160; P = 0.165] (triple therapy as a reference). Mortality was not significantly different (aOR, 1.370; 95% CI, 0.790-2.360; P = 0.258). Stent thrombosis was significantly different between the groups (aOR, 3.310; 95% CI, 1.040-10.500; P = 0.042) (triple therapy as a reference). In conclusion, for patients on OAC therapy who underwent PCI, periprocedural triple therapy may be safe with respect to in-hospital bleeding risks. However, further investigations are warranted to establish the safety and efficacy of periprocedural triple therapy.

Prior randomized controlled trials (RCT) evaluating the optimal antithrombotic therapies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not been powered to evaluate ischemic outcomes. We compared double therapy with oral anticoagulation (OAC) and a P2Y12 inhibitor to triple therapy with an OAC + dual antiplatelet therapy in patients with AF requiring PCI. Using PRISMA guidelines, we searched for RCTs including patients with AF as an indication for OAC and undergoing PCI or medical management of acute coronary syndrome. The results were pooled using fixed-effects and random-effects models to estimate the overall effect of double therapy versus triple therapy on ischemic and bleeding outcomes. We identified four RCTs, comprising 10,238 patients (5,498 double therapy, 4,740 triple therapy). Trial-reported major adverse cardiovascular events were similar between double therapy and triple therapy (fixed effect model OR 1.09, 95% CI 0.94-1.26). However, stent thrombosis (61/5,496 double therapy vs. 33/4738 triple therapy; fixed effect model OR 1.57, 95% CI 1.02-2.40; number needed to treat with triple therapy = 242) favored triple therapy. Bleeding outcomes were less frequent with double therapy (746/5470 vs. 950/4710; fixed effect model OR 0.59, 95% CI 0.53-0.65; number needed to harm with triple therapy = 16), but with significant heterogeneity (Q = 8.33, p = .04; I2 = 64%), as were intracranial hemorrhages (19/5470 vs. 30/4710; fixed effect model OR 0.54, 95% CI 0.31-0.96). Double therapy in patients with AF requiring OAC following PCI or Acute coronary syndrome has a significantly better safety profile than triple therapy but may be associated with a modest increased risk of stent thrombosis.

Objective: To compare the safety and efficacy of double therapy (DT) (no aspirin) versus triple therapy (TT) (with aspirin) antithrombotic drugs in patients with atrial fibrillation and acute coronary syndrome or underwent percutaneous coronary intervention (PCI).Methods: We searched PubMed, Cochrane, Scopus, and Web of Science for relevant articles from inception to December 2020. We conducted the analysis of dichotomous outcomes using risk ratio (RR) and relative 95% confidence interval (CI), while the continuous outcomes were analyzed using mean difference (MD) and relative 95% CI. Heterogeneous outcomes were analyzed with random-effects model, and homogeneous data were analyzed with fixed-effects model. We assessed the risk of bias among the included studies by using Cochrane’s risk of bias tool.Results: A total of five studies were included. Regarding Major or Minor Bleeding, the overall risk ratio was significantly lower with DT group compared with TT group (RR=0.60 [0.45, 0.81], (P = 0.07)). For the safety endpoint (TIMI major or minor bleeding, TIMI major bleeding) favored DT group over TT group, respectively (RR=0.60 [0.45, 0.81], (P = 0.07)); (RR= 0.55 [0.43, 0.70], (P < 0.01)). Intracranial hemorrhage did not differ between both groups (RR=0.62 [0.37, 1.05], (P = 0.07)). The efficacy endpoint, all-cause death showed no significant difference between both groups (RR=1.08 [0.89, 1.31], (P = 0.42)). There were no significant differences between two groups in cardiovascular death, stent thrombosis, myocardial infarction and stroke, respectively (RR=1.10 [0.86, 1.41], (P = 0.43); (RR=1.40 [0.92, 2.12], (P = 0.11); (RR=1.20 [0.98, 1.49], (P = 0.08); (RR=0.95 [0.66, 1.37], (P = 0.79).; respectively).Conclusion: Compared with triple antithrombotic therapy, double antithrombotic therapy is associated with lower bleeding risks, including minor and major bleeding, but the incidence of efficacy endpoints was similar between both groups.  Â

Optimal Antithrombotic Therapy in Patients Receiving Long-term Oral Anticoagulation Requiring Percutaneous Coronary Intervention: “Triple Therapy” or “Triple Threat”

A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/prednisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11, 1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel-reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8 +/- 13.7 years (range 17.6-78). The mean donor age was 34.0 +/- 20.1 years (range 0.3-75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 +/- 8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow-up was 22 +/- 4 months (range 12-29). Overall one-year actual patient survival was 94%. Overall one-year actual graft survival was 87%. Patients starting on double therapy had a one-year actual patient survival of 96% and a one-year actual graft survival of 92%. Patients starting on triple therapy had a one-year actual patient survival of 91% (P = ns compared with double therapy), and a one-year actual graft survival of 82% (P < 0.02, compared with double therapy). Overall results with first cadaver transplants included a one-year actual patient survival of 94% and one-year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P < .07). The incidence of steroid-resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8 +/- 0.8 mg/dl. The mean BUN was 33 +/- 21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was 192 +/- 49 mg/dl. A total of 56% of the patients are off prednisone, and 35% of the patients are not taking any antihypertensive medications. Other complications included cytomegalovirus--14%; new-onset diabetes--16% (half of which was reversible); and posttransplant lymphoproliferative disorder--1%.(ABSTRACT TRUNCATED AT 400 WORDS)

Dual antithrombotic therapy on early clinical outcomes in patients with atrial fibrillation after percutaneous coronary intervention: a nationwide study in the era of NOAC

Trifecta or Triple Threat? The Challenge of Post-PCI Management in Patients Receiving Chronic Oral Anticoagulant Therapy

The objective of antiretroviral therapy is to obtain an almost complete and durable suppression of viral replication in all compartments to facilitate recovery of the immune system. We assessed the virologic effect in plasma, tonsillar tissue, and cerebrospinal fluid (CSF) in 94 HIV-1-infected patients with CD4 counts >500 x 106 cells per liter and viral load >5000 copies/ml randomly assigned to triple antiretroviral therapy (two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor) versus double therapy (two NRTIs). We also analyzed the immunologic recovery in this cohort of patients. Lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to HIV-1 specific antigens, and other immunophenotypic markers were analyzed. The proportion of patients who achieved a decrease in HIV RNA levels to <200 copies/ml was significantly greater in the triple therapy group than in the two drug groups (p =.0002 for each pair-wise difference). At week 52, tonsillar tissue HIV RNA from 5 patients treated with triple therapy was lower than the limit of detection, whereas the mean +/- standard error in patients with double therapy (n = 5) was 5.03 +/- 0.34 copies/mg/tissue. In all 10 patients, CSF viral load (VL) was <20 HIV-1 RNA copies/ml at week 52. CSF cell counts and protein levels tended to decrease after 52 weeks of antiretroviral therapy. After 1 year of therapy, 13 of 21 patients (62%) in the double-therapy groups (zidovudine plus lamivudine [n = 9] and stavudine plus lamivudine [n = 12]) had evidence of M184V mutation. None of the 10 samples of patients receiving triple therapy could be amplified because of low HIV RNA levels. The mean increase in CD4 cells at week 52 was greater in the stavudine and lamivudine and indinavir group than in the double-treatment arms (186 versus 67 and 102, respectively; p =.03). In patients treated with triple therapy, the increase in naive T cells (CD4 and CD8) was greater than in patients treated with double therapy. Markers of activation decreased further in patients treated with the regimen that included protease inhibitors. Proliferative responses to HIV-1 p24 antigen were never recovered after double or triple therapy. Our study suggests that even in very early stages of HIV-1 disease only therapy with two NRTIs and one protease inhibitor reduces plasma, lymphoid tissue, and CSF VL to undetectable levels. HIV-1-related immune system abnormalities improved but were still defective after 1 year of antiretroviral therapy.

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A randomized trial was performed with the aim to compare two immunosuppressive treatment schedules in adult recipients of first cadaveric renal transplants. A total of 229 patients were randomized to double therapy with cyclosporine and prednisolone and 234 patients were randomized to triple therapy with cyclosporine, azathioprine, and prednisolone. Minimum follow-up was 4 years. The actuarial 5-year patient survival was 79.8% in the double therapy group and 82.3% in the triple therapy group (n.s.). The corresponding graft survival figures were 54.4% and 59.6% in the two groups, respectively (n.s.). There were no differences between the groups regarding cause of death or cause of graft loss. Renal function as determined by serum creatinine did not differ between the groups and was stable throughout the observation period. Azathioprine was instituted in a total of 51 patients randomized to double therapy. This subgroup of patients had a patient and graft survival not different from the remaining patients randomized to double therapy or from the patients randomized to triple therapy. There were no differences between the double and triple therapy groups regarding incidence and timing of acute rejection or infections. The incidence of other medical diseases and adverse events such as nephrotoxicity or malignancy did not differ between the groups. Azathioprine-induced leukopenia was uncommon (19 episodes in the triple therapy group). In a multivariate analysis of the whole series the only covariates that significantly influenced graft survival were age of recipient and occurrence of acute rejection, while among other factors treatment schedule did not. Thus this prospective study, in accordance with previous such studies, failed to find support for the use of triple therapy as first choice immunosuppression in first cadaveric renal transplantation. However, the study could not rule out the possibility that some patients at risk for the development of irreversible rejection or nephrotoxicity of CsA might benefit from the addition of azathioprine to the treatment schedule.

Antithrombotic treatment strategies after PCI