August 2020

Synopsis: The POPular TAVI trial was a randomized open-label trial in 17 separate European sites of oral anticoagulation (OAC) with either a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC) with or without clopidogrel after transcatheter aortic valve implementation (TAVI). Patients received therapy for 3 months and were then followed for one year. The primary outcomes were bleeding of any type and non-procedure related bleeding, while the secondary outcomes included a composite measure of death from cardiovascular causes, non-procedure related bleeding, stroke and myocardial infarction.

At 12-month follow-up, bleeding of any type was significantly less frequent in patients receiving only OAC (21.7%) compared to those receiving OAC plus clopidogrel (34.6%) (RR 0.63; 95% CI 0.43-0.90; p=0.01). Non-procedure related bleeding occurred in 34 patients (21.7%) on OAC monotherapy and in 53 (34.0%) patients receiving OAC and clopidogrel (RR 0.64; 95% CI 0.44-0.92; p=0.02). Additionally, a noteworthy difference was found in the composite secondary outcome: patients receiving OAC monotherapy were less likely to experience death from cardiovascular causes, non-procedure related bleeding, stroke and myocardial infarction (31.2%) compared to those receiving OAC plus clopidogrel (45.5%) (RR 0.69). Briefly, these initial results indicate that OAC plus clopidogrel compared to OAC monotherapy leads to an increase in all bleeding (procedural and non-procedural) without reducing the risk of ischemic stroke or myocardial infarction. 

There are several important limitations to these conclusions. First, the study is underpowered with an N of 313 patients enrolled. Secondly, we do not know how frequently the OAC was discontinued peri-procedurally based at the discretion of the clinical team. Additionally, further analyses should stratify results based on pre-operative indication for anticoagulation (e.g. atrial fibrillation), and compare patients receiving VKAs versus DOACs, instead of grouping them together. Finally, a more complete analysis would consider the timeline of stroke in this population. Notably, 25% of all strokes in this study occurred in the first 24 hours after TAVI, which suggests that the etiology of stroke in this subset of patients was more likely embolization of valvular, aortic or femoral calcification. Because strokes that occur later are more often due to valve thrombosis, they may be more treatable with antithrombotic therapy and thus more relevant to the clinical question here.

Considering these important limitations, the POPular TAVI trial suggests that the addition of clopidogrel to OAC following TAVI results in increased bleeding risk, both at one month and one year following valve implantation.  

Synopsis: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Previously, treatment for HCC relied on sorafenib, which is associated with a modest survival benefit and significant systemic toxicities. The IMbrave150 trial was conducted as an open-label phase 3 randomized trial to compare the safety and efficacy of atezolizumab plus bevacizumab against sorafenib in patients with unresectable HCC who had not previously received systemic therapy. The end points were overall survival and progression free survival with secondary end points of objective response rate, duration of response, and time to deterioration of quality of life and functioning per the patient. Atezolizumab targets PD-L1 to ultimately reverse T-cell suppression and bevacizumab targets vascular endothelial growth factor and may enhance anti-PD-L1 efficacy.

Patients with preserved liver function (Child-Pugh class A) were randomly assigned to either atezolizumab plus bevacizumab (336 patients) or sorafenib (165 patients) and stratified by geographic region, macrovascular invasion or extrahepatic spread, baseline AFP, and ECOG performance status. Patients continued treatment until unacceptable toxic effects occurred or there was loss of clinical benefit. Tumors were assessed by CT and MRI at baseline then set time intervals. 

Ultimately, this trial showed treatment with atezolizumab plus bevacizumab was associated with significantly better overall survival and progression free survival outcomes than sorafenib. Overall survival at 6- and 12- months was significantly greater with atezolizumab–bevacizumab versus sorafenib (67.2% (95% CI, 61.3 to 73.1) versus 54.6% (95% CI, 45.2 to 64.0) at 12 months). Median progression free survival was also significantly different, 6.8 months (95% CI, 5.7 to 8.3) versus 4.3 months (95% CI, 4.0 to 5.6) in the respective groups. Eighteen patients (5.5%) in the atezolizumab–bevacizumab group, as compared with no patients in the sorafenib treatment group, had a complete response. 

Serious adverse events occurred more frequently with atezolizumab– bevacizumab (125 patients [38.0%]) than with sorafenib (48 patients [30.8%]). 

Taken together, in patients with HCC, atezolizumab– bevacizumab resulted in a better overall and progression free survival as compared to sorafenib. While this study was limited by open label design (and thus lack of placebo controls), the demonstrable efficacy of this drug combination in non-resectable HCC appears clear. Further work is needed in the adjuvant/neoadjuvant settings for resectable HCC, as well as in patients with poorer liver function.

Synopsis: A must read for anyone rotating through transplant this year. This NEJM article summarized antibody mediated rejection (AMR) for solid organ transplants. As you will often hear the teams discuss on the transplant service, donor-specific anti-HLA antibodies are a key (but not required) component of the diagnosis of AMR – heart transplant is the only organ system that requires donor-specific antibodies. In addition, non-HLA antibodies, such as MHC peptides and angiotensin II may be useful in making a diagnosis. Biopsy is useful – looking for microvascular inflammation (capillary dilation, cytoplasmic swelling, and the presence of inflammatory cells). Additionally C4d staining (from the complement activation of cell destruction you learned ages ago) is a specific but not very sensitive marker of inflammation. Current treatment options include plasmapheresis, IVIG, or steroids.

Turn your attention to the later half of the article where the authors discuss research efforts to for precision medicine in transplant. Things potentially on the horizon include:

1. Noninvasive biomarkers in blood or urine
2. Donor derived cell-free DNA on plasma
3. Therapeutics targeting antibody production (rituximab, anti-C5 antibodies, etc.)