CoronaVac, BNT162b2 and heterologous COVID-19 vaccine outcomes in patients with ventricular assist device

Abstract

Background:

A consensus has not yet been reached regarding which COVID-19 vaccine program should be applied in patients with ventricular assist device (VAD). Our aim was to assess the clinical outcome of inactivated, mRNA and heterologous vaccine program in patient with VAD.

Methods:

In this retrospective and cross-sectional study; adult patients who underwent VAD implantation between January 2012 and September 2021 and received any vaccine that were used in Republic of Türkiye for COVID-19, were included. The patients were divided into three groups according to the type of vaccine; “inactivated,” “mRNA” and “heterologous.” Clinical outcomes were analyzed.

Results:

Eighteen patients were in each group in the “inactivated,” “mRNA” and “heterologous” groups. Mean age was 51.6 ± 12 years in “inactivated” group, 42.5 ± 15.5 years in “mRNA” group and 41.1 ± 15.4 years in “heterologous” group. There was no significant difference between the groups in age, gender, body surface area, body mass index and etiology (p > 0.05). After last dose of vaccines, the number of patients had COVID-19 positive test were three (16.7%), one (5.6%), and two (11.1%) in “inactivated,” “mRNA” and “heterologous” groups, respectively. Pump thrombosis was seen in two patients in “mRNA” group and one patient in “heterologous” group. No pump thrombosis was seen in “inactivated” group. COVID-19-related death or intubation was not observed.

Conclusion:

All vaccine that used for COVID-19 are safe and effective in patients with VAD. In countries that give priority to inactivated vaccines, mRNA vaccines may then be made as boosters.

Visual abstract.

Distribution of patients according to their vaccine status

Introduction

Ventricular assist devices (VAD) are the treatment option in advanced heart failure, which is one of the most important causes of detrimental complications due to coronavirus disease 2019 (COVID-19).^1,2 Although the reasons remain unclear, patients with VAD have impaired immune systems and are susceptible to infection.³ Presence of infection in patients with VAD is associated with serious morbidity such as pump thrombosis, and mortality.⁴

Currently, inactivated and messenger-RNA (mRNA) vaccines are used in Republic of Türkiye. Although the safety and efficacy of these vaccines are high, its relation with thromboembolic events is controversial.⁵ Limited information is available on the outcomes of vaccination in VAD patients who are on long-term anticoagulants and are at risk for pump thrombosis. Moreover, there is no consensus yet on which vaccination program should be used in VAD patients.

In this study, 6-month outcomes of the use of COVID-19 vaccines (inactivated, mRNA, and heterologous) in VAD patients are reported.

Material and methods

In our retrospective and cross-sectional study; adult patients who underwent VAD implantation between January 2012 and September 2021 and received any vaccine that were used in Republic of Türkiye for COVID-19, were included. Patients who had COVID-19 before or during being vaccinated, have not completed at least two dose of vaccinations, under 18 years old, and refused to be participant in the study were excluded from the study. In the COVID-19 pandemic, the two groups of vaccines most widely used in Republic of Türkiye were administered to our patients. The emergency use approval in Republic of Türkiye for CoronaVac (Sinovac Biotech Co., Ltd., Beijing, China) was issued in January 2021, and for BNT162b2 (Pfizer-BioNTech, Mainz, Germany) in March 2021. Within these dates, vaccinations started in the order determined by the government. Since our patients were one of the first groups to be vaccinated, vaccinations have started as of these dates.

The patients were divided into three groups according to their vaccination status. The patients vaccinated with only the inactivated vaccine (CoronaVac) (two or three doses) were classified as “inactivated,” those with only BNT162b2 (two or three doses) were classified as “mRNA,” and those with a single or double dose of mRNA vaccine after at least double dose inactivated vaccine were classified as “heterologous.” Age, body mass index, body surface area, gender, etiology, device type, follow-up time, history of COVID-19, cerebrovascular event, pump thrombosis, driveline infections were analyzed.

At least 14 days after last dose of vaccine, patients with positive SARS-CoV-2 reverse transcription-polymerase chain reaction test from respiratory tract samples were accepted as COVID-19 positive.

The density of diagnosis of patients with COVID-19 and the fluctuations in COVID-19 trends in Republic of Türkiye were also analyzed.⁶

The study was approved by the local ethical committee (ACH E1/2551/2022 20.04.2022).

Statistics

Statistical analyzes were performed using the SPSS version 23 (IBM Corp., Armonk, NY, USA). For normal distribution, the Levene test was used for continuous variables and one-way ANOVA was used to determine if there was a difference between independent groups. For non-normal distribution, Kruskal-Wallis test was used. Cox-regression analysis was used to assess the effect of vaccine types. Arithmetic mean and standard deviation for numerical variables with normal distribution as the descriptive statistics; median, minimum and maximum values for the data with non-normal distribution; number and percentage values for the attribute variables are given. p < 0.05 was considered statistically significant.

Results

Fifty-four patients with VAD who received any COVID-19 vaccine were included in our study. Eighteen were in “inactivated” group (seven of the patients received two doses, 11 received three doses); 18 in “mRNA” group (10 patients received two doses, eight received three doses); 18 patients in the “heterologous” group (12 patients with two doses of inactivated and a single dose of mRNA as a booster; 6 patients with two doses of inactivated and two doses of mRNA as a booster). The baseline characteristics of the patients are summarized in Table 1. Mean age was 51.6 ± 12 years in “inactivated” group, 42.5 ± 15.5 years in “mRNA” group and 41.1 ± 15.4 years in “heterologous” group. There was no significant difference between the groups in age, gender, body surface area, body mass index and etiology (p > 0.05). The VADs used in this study were HeartWare HVAD (Medtronic Inc., Minneapolis, Minnesota, USA) and Heartmate III (Abbott Inc., Chicago, Illinois, USA). As biventricular assist device (BiVAD); one patient had Heartware in the “inactivated” group, while one patient had Heartware and two patients had Heartmate three in the “mRNA” group. All other patients had left-sided VAD (LVAD). Follow-up periods after the last dose of vaccine were 189 ± 80 days in the “inactivated” group, 155 ± 96 days in the “mRNA” group, and 169 ± 60 days in the “heterologous” group. There was no difference in the follow-up times between the groups (p > 0.05).

Table 1.

Demographics of the patients.

	Inactivated (n = 18)	mRNA (n = 18)	Heterologous (n = 18)
Age (years)	51.6 ± 12 (22–67)	42.5 ± 15.5 (18–65)	41.1 ± 15.4 (18–66)	p > 0.05
Body mass index (kg/m2)	26.9 ± 4.5	24.4 ± 5	25.3 ± 3.5	p > 0.05
Body surface are (m2)	1.8 ± 0.1	1.8 ± 0.1	1.8 ± 0.2	p > 0.05
Male gender (%)	13 (72.2%)	16 (88.9%)	13 (72.2%)	p > 0.05
Etiology				p > 0.05
Dilated CMP	9 (50%)	10 (55.6%)	14 (77.8%)
Ischemic CMP	8 (44.4%)	7 (38.9%)	6 (16.7%)
Hypertrophic CMP	1 (5.6%)	0	0
Postpartum CMP	0	1 (5.6%)	1 (5.6%)
Device type				p > 0.05
Heartware	4 (22.2%)	7 (38.9%)	5 (27.8%)
Heartmate 3	13 (72.2%)	8 (44.4%)	13 (72.2%)
BiVAD Heartware	0	1 (5.6%)	0
BiVAD Heartmate 3	1 (5.6%)	2 (11.1%)	0
Follow-up after last dose of vaccine (days)	189 ± 80 (55–331)	155 ± 96 (35–300)	169 ± 60 (61–239)	p > 0.05

CMP: cardiomyopathy; BiVAD: biventricular assist device.

The number of patients had COVID-19 positive test were three (16.7%), one (5.6%), and two (11.1%) in the “inactivated,” “mRNA”, and “heterologous” groups, respectively (p > 0.05) and none of them were hospitalized (Table 2). The type of vaccine did not make any difference in patients in terms of getting COVID-19 after vaccine application (p = 0.769) (Figure 1). The left hemiplegic-cerebrovascular event was observed in one patient in “mRNA” group. Pump thrombosis was seen in two patients in “mRNA” group and one patient in “heterologous” group. No pump thrombosis was seen in “inactivated” group. Driveline infections (DLI) were seen in four patients in the “inactivated” group, one patient in the “mRNA” group, and five patients in the “heterologous group. While drivelines with infection in all groups were rerouted, only two (10.2%) of the patients in the “heterologous” group were rerouted (Table 2).

Table 2.

Presence of COVID-19 and post-vaccination adverse events in patients with VAD.

		Inactivated (n = 18)	mRNA (n = 18)	Heterologous (n = 18)
COVID-19 after last dose of vaccine	Negative	15 (83.3%)	17 (94.4%)	16 (88.9%)	p > 0.05*
	Positive at home	3 (16.7%)	1 (5.6%)	2 (11.1%)	p > 0.05*
CVE after vaccine		0 (0%)	1 (5.6%)	0 (0%)	p > 0.05**
Pump thrombosis after vaccine		0 (0%)	2 (11.1%)	1 (5.6%)	p > 0.05**
Driveline infection	Exit site drainage	0 (0%)	0 (0%)	3 (16.7%)	p > 0.05**
	Rerouting	4 (22.2%)	1 (5.6%)	2 (11.1)	p > 0.05**

CVE: cerebrovascular events; VAD: ventricular assist device.

^*One-way ANOVA. **Kruskal Wallis Test

Figure 1.

Freedom from COVID-19 after last dose of vaccine.

Although death due to right heart failure was observed in one patient during the follow-up period in “inactivated” group, COVID-19-related death or intubation was not observed. One patient with LVAD and one patient with BiVAD (both of them had no vaccine) underwent heart transplantation and no adverse events related to COVID-19 were encountered in the follow-up. Booster doses were not administrated before or after transplant.

After the start administration of “inactivated” vaccine in January 2021 and “mRNA” vaccinations in March 2021, three peak points were seen in Republic of Türkiye; in April and September/October of 2021 and in January/February of 2022. An overlap was seen between these periods of infection and COVID-19 positive test of patients with VAD (Figure 2).

Figure 2.

COVID-19 positive patients with VAD and in Republic of Türkiye.

Discussion

In this study, patients had inactivated vaccine or mRNA vaccine or prime booster vaccination using two dose of inactivated vaccine and one dose of mRNA vaccine booster (heterologous) were analyzed. In “mRNA” group, number of patients with COVID-19 positive test was lower than the other groups but statistical significance could not be reached. Besides, with all vaccine regimen, the disease was not severe enough to require hospitalization. Our study design proceeded from two main branches after administration of different types of vaccines in patient with VAD. The first was the vaccine effect (protection from COVID-19). We waited for the vaccination program to be completed so that we could reach the theoretically effective dose of the vaccine.⁷ Thus, while it has been reported in the literature that the protective effect of the first dose vaccines was low, we wanted to show the level of protection with booster doses. The second arm was vaccine side effects (pump thrombosis, cerebrovascular event, etc.). In this respect, it was important to collect the data from the first dose in order to show the side effects that may occur even after the first dose. To our knowledge, this is the first study to show the outcomes of inactivated, mRNA and heterologous vaccines in patients with VAD.

Different vaccine regimens are applied in every country in the world. Some countries use inactivated and some use mRNA vaccines, while others have both vaccines. In Republic of Türkiye, in accordance to the government policy, primarily inactivated vaccines were provided and applied. Subsequently, mRNA vaccines were also used and heterologous vaccine programs were formed. Vaccine data in particularly vulnerable populations are valuable, as inactivated vaccines and mRNA vaccines are used together, as COVID-19 protection is provided by two different pathways. All vaccines against COVID-19 in market are safe and effective to prevent the disease and mortality.^8–10 In a study assessing the immunogenicity of BNT162b2 vaccine in patients with VAD, anti-spike IgG were positive in 83% of patients 6 months after last dose of vaccine.⁷ This result was also supported by a study in which IgG seropositivity was higher in the BNT162b2 group than in the CoronaVac group.¹¹ In a large-scale population study using BNT161b2 as a booster dose after two doses of CoronaVac vaccine; it has been found that only after CoronaVac vaccine, the protection can be reduced, and the vaccine effect can be strengthened with a booster dose of BNT162b2. It has been found that the use of heterologous vaccines, especially in elderly patients, will help prevent both infection and serious adverse effects of disease.¹² In another study from Chile that used homologous and heterologous booster vaccines, both vaccination methods gave better results than the no vaccine population and the heterologous booster method was found to be more effective than the homologous method.¹³ In a study that compared two mRNA vaccines; mRNA1273 vaccine may be more effective than BNT162b2.¹⁴ It has been shown that both mRNA vaccines were effective, especially in the immunosuppressed and male population, which were in the high-risk group for breakthrough infection. In the literature, to our knowledge, there is no study yet on the CoronaVac vaccine used in patients with VAD. In our study, while the rates of patients who did not have COVID-19 positive test in the “inactivated” and “mRNA” groups were around 75%, this rate approached 90% in the “heterologous” group. Although there is no statistical significance due to the small number of patients, the patients who were severely ill enough to require hospitalization among the patients had COVID-19 positive test were not seen in the “heterologous” group. In the early days of the pandemic, we informed our patients that they should pay particular attention to primary protection. Moreover, possible high seropositivity was achieved with the initiation of vaccination programs, and high mortality rates may have decreased in other studies conducted before vaccination programs.¹⁵

The patients with VAD have impaired cellular immunity and are susceptible to infections.³ Before the vaccination programs, in VAD patients, hospitalization and mortality of COVID-19 were high as 60% and 20%, respectively.¹⁵ The biggest advantage of the vaccination program is undoubtedly that it has ensured the protection of such patients. No mortality was observed in any of our vaccine groups. The fact that no mortality in vaccinated patients indicates that it is important to be vaccinated regardless of the type of vaccine in VAD patients who are prone to infection and the undesirable effects of infection; it also prevents these patients, who are also transplant candidates, from being frail during their preparation for transplantation.

Thrombosis cases associated with COVID-19 are common, it has been reported that thrombosis can also be seen in some series, albeit rarely, after COVID-19 vaccine. Although the underlying mechanism of post-vaccine thrombosis has not yet been fully elucidated, it is thought to be related to pathways that promote platelet and coagulation pathway.¹⁶ We encountered pump thrombosis in our two different vaccine groups. The international normalized ratio (INR) of all patients were within therapy limits (2.5–3.5) at the time of post-vaccine pump thrombosis, and tissue plasminogen activator (tPA) was administrated to all of them after hospitalization. Thrombosis of all patients resolved after tPA and they were discharged without any problem. Whether this situation was related to the vaccine or not, needs to be investigated in larger series.

We have noticed that the need for driveline translocation (rerouting) has increased in the patients with VAD since the vaccination program started (however, this data is not available in the article). After COVID-19 vaccine, especially mRNA vaccine, skin lesions such as angioedema urticaria and pruritus can occur.^17,18 Especially considering the rate of driveline infection in the “combine” group; we can speculate whether COVID-19 vaccines could cause a late-term hypersensitivity reaction and increase the need for translocation by causing the progression of driveline infections that were previously observed in mild form.

We have used telemedicine to follow-up our patients during the pandemic. The mechanical circulatory support system coordinators have contacted with our patients periodically by phone and e-mail. In these interviews, in addition to lockdown the country, we have called them to stay home and given information about prevention. We have followed-up our patients’ COVID-19 status, INR levels, pump information via telemedicine. This helped us to update our data and to maintain close surveillance. In addition to vaccine shield, we think that basic protective cautions such as maintaining social distance, wearing a mask, staying away from crowded areas are also important to protect from disease. Because, by looking at the trend of the number of the patients had COVID-19 positive test in Republic of Türkiye, there was a similarity in the number of patients with VAD who admitted to our center as COVID-19 during the relaxation of the restrictions corresponding to those periods. Moreover, these precautions could help to decrease the rate of Covid-19-positive patients in our cohort.

Limitations

First, this study is a single center design and has small group of patients. More information may be obtained with future multicenter studies involving such patients, which are a small group in number. Second, the immunogenicity provided by the vaccine has not been demonstrated in plasma.

Conclusion

Inactivated and mRNA vaccines used in the COVID-19 pandemic are safe and effective for VAD patients. In cases where the first two doses are given as inactivated vaccines, mRNA vaccines can be considered as a booster. Moreover, we think that the social isolation rules, which are at least as effective as the vaccine, should continue in special patient groups during the pandemic period.