• „ ORIGINAL ARTICLE

Protamine sulfate during transcatheter aortic valve implantation (PS TAVI) — a single-center, single-blind, randomized placebo-controlled trial

Karol Zbroński1, Kajetan Grodecki1, Roksana Gozdowska1, Ewa Ostrowska1, Julia Wysińska1, Bartosz Rymuza1, Piotr Scisło1, Radosław Wilimski2, Janusz Kochman1, Krzysztof J Filipiak1, Grzegorz Opolski1, Zenon Huczek1

11st Department of Cardiology, Medical University of Warsaw, Warszawa, Poland

2Department of Cardiac Surgery, Medical University of Warsaw, Warszawa, Poland

INTRODUCTION

Transcatheter aortic valve implantation (TAVI) is an increasingly popular treatment method for patients with severe, symptomatic aortic stenosis (AS). In a plethora of studies either a clear benefit or non-inferiority was demonstrated in comparison to the gold standard — surgical aortic valve replacement — across almost all spectrums of AS patients [1]. Despite the fact, that many aspects of the antithrombotic treatment before and after TAVI have been studied, routine use of protamine sulfate (PS) to reverse the effect of the unfractionated heparin (UFH) was never included in those analyses.

Based on an expert consensus [2], UFH should be administered in every patient and should be reversed with PS after transapical and transfemoral TAVI except for transfemoral cases with minimal bleeding risk. The clinical practice, however, differs between centers [3, 4]. The impact of PS on bleeding and thromboembolic complications is unknown and reports of the pro-thrombotic effect of the PS have been published in different clinical settings [5–7]. Hemorrhagic complications (at least major bleedings according to Valve Academic Research Consortium [VARC] criteria [8]) increase mortality after TAVI [9] and are relatively frequent ranging from 4.7% up to 77% [10–12]. No randomized trials assessing the influence of PS on bleeding rates after TAVI have been published to date. In order to comply with the rule of thumb — “when in doubt, randomize” — a clinical, placebo-controlled trial is required in order to properly assess the impact of protamine sulfate administration.

METHODS

Trial design and funding

The protamine sulfate during transcatheter aortic valve implantation (PS TAVI) is a single-center, single-blind randomized placebo-controlled trial in which routine PS administration to reverse UFH was compared to placebo. The study was investigator-initiated and did not receive any funding from the industry. Informed consent was obtained from all participating patients and the local ethics committee granted permission for the study (approval number KB/212/2016). The study protocol is available on ClinicalTrials.gov (NCT02974660). The study design is presented on Figure 1.

Patients, randomization, and procedures

The study aimed to include patients with severe, symptomatic aortic stenosis (aortic valve area [AVA] <1.0 cm2 or indexed valve area less than 0.6 cm2/m2 or mean gradient >40 mm Hg or maximum jet velocity >4.0 m/s or velocity ratio <0.25), qualified by the Heart Team to a transfemoral TAVI with a planned application of pre-close devices such as Prostar® or Proglide®. The exclusion criteria were lack of informed consent, participation in another clinical trial, and known allergy to protamine sulfate.

Both mechanically- and self-expandable aortic valve prostheses of the second generation were used. In all cases, transfemoral access with at least two pre-close devices was applied. The procedures were performed in hybrid operating rooms under general anesthesia or local anesthesia with conscious sedation. After obtaining the vascular access, all patients received UFH at the dose of 100 IU/kg with the target activated clotting time (ACT) of 250–300 seconds.

At the moment of the optimal valve implantation, eligible patients were randomly assigned using the envelope method to either protamine sulfate or normal saline. The PS was administered in a slow bolus at the dose of 1 mg per 100 IU of unfractionated heparin administered within the last 30 minutes plus 0.5 mg per 100 IU of the UFH administered earlier. The successful reversal of heparin was confirmed by ACT measurements at baseline, after UFH boluses, before and after PS administration.

The type and number of preclose devices was noted as well as potential issues with the closure, including extravasation of the contrast in the final femoral angiography, device malfunction, need for balloon angioplasty, stent implantation, or emergent surgical cut-down.

In terms of antithrombotic treatment before and after TAVI, patients without indications for chronic oral anticoagulation (OAC) were given loading doses of 300 mg of aspirin and clopidogrel within 24 hours before TAVI, and then continued 75 mg daily after the procedure. In patients requiring chronic OAC, the treatment was stopped 2–3 days before the procedure in order to obtain an international normalized ratio of <2 in case of vitamin K antagonists (VKA) and 1–2 days before the procedure depending on the renal function in case of non-vitamin K antagonists. After TAVI the oral anticoagulation was restarted as soon as deemed safe, with additional bridging with low-molecular-weight heparin in patients receiving VKA.

Endpoints and definitions

The primary endpoint of the study was a composite of life-threatening and major bleeding complications according to VARC-2 at 48 hours after the procedure. The secondary endpoints were major and minor bleedings according to VARC-2 at 48 hours after the procedure, all-cause mortality at 30 days, a drop in hemoglobin concentration 48 hours after the procedure, the length of the hospitalization (the time from the index procedure to discharge), and thromboembolic events (stroke, transient ischemic attack, myocardial infraction) within 48 hours after the procedure. Coronary artery disease was defined as the presence of at least one lesion >70% in the epicardial coronary vessel >1.5 mm (>50% for left main), history of myocardial infarction, previous percutaneous coronary intervention, or coronary artery bypass grafting. Successful closure of the access artery was defined as obtaining proper hemostasis with no residual bleed, without device malfunction or a need for prolonged balloon inflation or covered stent implantation. Access-site and access-related vascular injury (ASARVI) was defined according to a modified classification by Sedaghat et al. [13]: type I, blush or minimal extravasation; type II, moderate extravasation (<5 mm); type III, major extravasation (>5 mm) including vessel perforation/rupture; and type IV, vessel dissection or occlusion.

Statistical analysis

Estimation was done based on the major and life-threatening bleeding rates from the historic material of the center (28%), that 100 patients are required to have a 90% chance of detecting a significant decrease in the primary outcome occurrence from 28% in the placebo group to 5% in the PS group. The primary analysis was performed in the intention-to-treat population.

Continuous variables, expressed as the median and interquartile range (IQR), were compared between the study and control groups using Mann-Whitney U-test. Shapiro-Wilk test was used to confirm or reject the normal distribution of each continuous variable. Categorical variables, expressed as counts and percentages, were compared using the Chi-square test or Fisher’s exact test, as appropriate.

A uni- and multivariable backward likelihood ratio logistic regression model was used to identify predictors of the primary and secondary endpoints. Variables from the univariate analysis (with a P value of ≤0.20 difference) were included in the multivariable analysis. Results are presented as odds ratio (OR) with 95% confidence intervals (CI).

All probability values reported are 2-sided and a value <0.05 was considered to be significant. All data were processed using the SPSS software, version 22 (IBM SPSS Statistics, New York, NY, USA).

RESULTS

Population

Of the 311 consecutive patients screened between December 2016 and July 2020 in one academic center, 85 (27%) underwent TAVI via an other-than-transfemoral or transfemoral with surgical cut-down access, 78 (25%) participated in other clinical trials and 48 (15%) did not consent to participation in the study. The study flow-chart is presented in Figure 2.

Overall, one hundred patients were included in the study. The median age was 82 years (IQR 77–85), there were 48 males (48%), almost 90% of patients had hypertension, 43% — diabetes, and approximately one-third (36%) was in New York Heart Association (NYHA) class III or IV. The median logistic EuroSCORE was 10.5 (IQR, 8–16). All the procedures were performed via transfemoral access and in all cases, a pre-close system was used. Detailed baseline data are shown in Table 1.

Protamine sulfate administration

Forty-seven subjects (47%) were randomized to protamine sulfate and 56 patients (56%) have received PS (cross-over: 9%; in all cases the reason for cross-over was due to operators’ decision). Median PS dose was 35 mg or 0.5 mg per 100 IU of UFH. There were no major differences between the PS and placebo group, except for the presence of moderate or severe mitral regurgitation (49% vs 30%, PS and placebo respectively, P = 0.07) as well as pre- and post-dilatation (pre-dilatation: PS — 45%, placebo — 68%, P = 0.03; post-dilation: PS — 26%, placebo — 46%, P = 0.04).

Primary endpoint

The primary composite endpoint of VARC-defined major and life-threatening bleeding was observed in 29 patients (29% of the study population, 21% of the PS cohort, and 36% of the control group, P = 0.13). Major bleeding occurred in 19 patients (19%, 13% of those randomized to PS, and 25% of the control group, P = 0.2). One disabling stroke (1%) and 2 transient ischemic attacks (2%) were reported. The 30-day all-cause mortality was 5%. A detailed list of study endpoints is presented in Table 1.

In a multivariable analysis of the primary endpoint occurrence, only serum creatinine (OR, 2.93 per 1 mg/dl increment; CI, 0.97–8.8; P = 0.06) has shown a trend towards statistical significance, while the remaining parameters included in the model: female gender (OR, 2.21; CI, 0.86–5.66; P = 0.1) and randomization to protamine sulfate administration (OR, 0.49; CI 0.92–1.2; P = 0.13) did not reach significance (Table 2).

Protamine sulfate and secondary endpoints and the per-protocol analysis

The impact of randomization to PS on VARC-defined major bleeding (OR, 0.45; CI, 0.2–1.3; P = 0.14, Table 3), any bleeding (OR, 0.55; CI 0.2–1.27; P = 0.16) as well as the remaining study endpoints also did not reach statistical significance (Table 4). Results of the per-protocol analysis are presented in the Supplementary material, Tables S1, S2, and S3.

DISCUSSION

Despite the long-lasting presence of protamine sulfate in the pharmacological arsenal of peri-procedural drugs in the field of interventional cardiology, it has never been studied in a randomized fashion in the setting of TAVI. Both bleeding and thromboembolic complications may potentially arise from PS administration, with the first being a result of potential rebound anticoagulation due to PS short half-life (7 minutes as compared to UFH’s 60–90 minutes), while the latter occurring due to possible rebound thrombosis after sudden UFH reversal [14]. In a study assessing UFH reversal with PS after carotid endarterectomy, a trend towards thrombosis and stroke was reported [5].

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