Clinical heart transplantation

Article Outline

Methods

Data Source

Study Design and Patient Population

Outcome Measures

Analysis

Results

Discussion

Limitations

Our Approach

References

Over 45 years have passed since the initial description of orthotopic heart transplantation (OHT) by Lower and Shumway.¹ Since their early description, OHT has become the gold standard treatment for patients with many forms of end-stage heart failure. Despite the success of OHT, the optimal surgical anastomotic technique remains in question.

Traditionally, most OHTs have been performed according to the biatrial anastomotic technique developed and described by Lower and Shumway.¹ The biatrial technique consists of performing a biatrial anastomosis whereby donor and recipient atrial cuffs are sewn together. Although biatrial anastomosis does not require separate caval anastomoses, and therefore saves time, potential problems include atrial dysfunction, sinus node dysfunction, valvular insufficiency and thrombus formation.

In response to these concerns, the bicaval technique (which consists of sewing separate caval anastomoses) was developed and introduced in the early to mid-1990s.^{[2], [3], [4], [5] and [6]} Studies comparing the two techniques have shown that the bicaval anastomotic technique leads to improved atrial function,^{[7] and [8]} lower rate of post-operative arrhythmias,⁹ decreased need for permanent pacing,¹⁰ decreased tricuspid regurgitation,^{[11], [12] and [13]} and in one series improved survival.¹⁴ As a result of this perceived superiority, the number of heart transplants conducted with the bicaval technique has increased steadily since 1995. In fact, in both 2004 and 2005, more adult bicaval transplants were performed than biatrial (Figure 1). Although early studies supported the use of the bicaval technique, all have been conducted at single centers with small numbers of patients. The United Network for Organ Sharing (UNOS) database is a nationwide, physician-overseen sample, which provides a unique opportunity to address these issues free of single institutional bias. We conducted a retrospective examination of the multi-institutional UNOS database to determine the influence of the anastomotic technique on short- and mid-term survival in patients receiving OHT. We hypothesized that no difference in survival would exist between the two techniques when examined on a large scale with a modern cohort.

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Figure 1. Trends in OHT type performed over time (shaded bars: biatrial technique; solid bars: bicaval technique). In addition, total adult OHT for reference is given (dashed line). As can be seen, bicaval OHT was described in 1993 and increased substantially after 1999. In 2004 and 2005, more bicaval transplants were performed than biatrial (based on OPTN data, September 2006).

Methods

Data Source

UNOS provided de-identified patient data (Standard Transplant Analysis and Research, STAR files) from the thoracic organ transplant registry for the years 1987 to 2005, with follow-up through September of 2006. The data include all patients in the USA undergoing thoracic organ transplantation and reported to the Organ Procurement Network during the time period. Unique center identity codes were included to allow examination of institutional volume.

Study Design and Patient Population

We conducted a retrospective review of the UNOS database from January of 1999 to December of 2005, with follow-up through September 2006. The time-points were chosen to identify a modern cohort of patients who underwent OHT after the widespread institution of the bicaval anastomatic technique (Figure 1). In this way, any bias related to the surgeon’s experience with the technique would be minimized. All first-time orthotopic heart transplant patients between the ages of 18 and 80 years were included. Patients were primarily stratified by anastomotic technique (biatrial vs bicaval). We excluded those patients with heterotopic transplants and those having undergone the orthotopic total anastomotic technique. We also excluded those without available data on their transplant technique.

Outcome Measures

Baseline demographic and clinical factors were recorded. The primary end-point was all-cause mortality during the study period. Secondary outcomes included length of hospital stay (LOS) and need for permanent pacemaker placement (PP). Centers were also arbitrarily stratified by mean annual institutional heart transplant volume to determine whether outcomes with technique varied by center volume.

Analysis

Comparisons of baseline characteristics between study groups were performed using Student’s t-test for continuous variables and the chi-square test for categorical variables. Cumulative survival was modeled using the Kaplan–Meier method with statistical differences between survival curves assessed using the log-rank (Mantel–Cox) test. Mortality was first assessed for all risk factors using a univariate model. Multivariate analysis was conducted using the Cox proportional hazards regression model. Significant univariate predictors of mortality were incorporated into the multivariate model in a stepwise fashion to assess the effect of technique on mortality. Only well-represented variables (<33% missing in the registry) were included in the multivariate analysis. In addition, uni- and multivariate logistic and linear regression analyses, when appropriate, were performed for all additional outcome variables.

Statistical significance was established at p < 0.05 (2-tailed) and all odds ratios and regression coefficients are presented with 95% confidence intervals. All statistical analyses were performed using Stata software, version 9.0 (StataCorp, College Station, TX).

Results

A total of 14,418 patients underwent first-time OHT during the study period. After exclusion of children (age <18 years, n = 1,831), those >80 years of age (n = 2), orthotopic total transplants (n = 482), heterotopic transplants (n = 4) and those without data on transplant technique (n = 139), the final study population was 11,931. Of these, 5,207 (43%) received the bicaval anastomotic technique. The bicaval technique increased in prevalence during the study period with the greatest proportion of patients receiving bicaval techniques in the years of 2004 and 2005 (Figure 1).

Both bicaval and biatrial patients were well matched for baseline characteristics, including age, gender, race and measures of co-morbidities, such as body mass index (BMI), creatinine level, whether they were hospitalized at time of transplant, and whether they were in an ICU at time of transplant (Table 1). In addition, patients were well matched for baseline hemodynamic variables pre-operatively. Importantly, ischemic time was not longer for bicaval patients.

Table 1.

Baseline Characteristics of Patients Undergoing OHT With Biatrial vs Bicaval Anastomotic Techniques

	Biatrial (N = 6,724)	Bicaval (N = 5,207)	p-valuea
Demographics
Mean age	52 (12)	52 (12)	0.50
Female	1,642 (24)	1,216 (23)	0.17
Black, Hispanic, Native American, Asian/Pacific Islanderb	1,502 (23)	1,294 (25)	<0.001
Comorbidities/acuity
Diabetes	1,337 (20)	1,048 (20)	0.94
Creatinine	1.4 (0.8)	1.4 (0.8)	0.53
BMI	26.3 (4.5)	26.3 (4.6)	0.3
Hospitalized prior to transplant	3,450 (51)	2,784 (53)	0.007
ICU prior to transplant	2,100 (31)	1,589 (30)	0.41
Pre-op inotropes	31.4 (12)	31.8 (12)	0.06
Donor age (years)	3.14 (1)	3.08 (1)	0.003
Ischemic time (hours)	2,483 (37)	2,171 (42)
Hemodynamic variables
Mean PA pressure	28.2 (10)	28.6 (10)	0.08
PVR	2.4 (1.9)	2.4 (1.9)	0.86
Cardiac index	1.6 (0.5)	1.5 (0.5)	0.36
TPG	9.4 (5.8)	9.5 (5.5)	0.65

Data expressed as N (%) or mean (SD). PA, pulmonary artery; BMI, body mass index; ICU, intensive care unit; pre-op, pre-operative; PVR, pulmonary vascular resistance (defined as: [mean PA pressure (mPAP) − pulmonary capillary wedge pressure (PCWP)]/cardiac output); TPG, transpulmonary gradient (defined as: MPAP − PCWP).
^a p-value is based on comparison between two groups by either chi-square or Student’s t-test (p ≤ 0.05 considered statistically significant).
^b Race or ethnic group was a variable present in the dataset.

Cumulatively, 2,364 patients died during the study period, generating an overall all-cause mortality of 20%. Although univariate analysis showed the biatrial group to have a higher overall mortality (24% vs 18%, p < 0.001), this relationship did not hold true after adjustment for confounders in the proportional hazards model (hazard ratio [biatrial] 1.06, p = 0.31) (Table 2). Strong predictors of mortality on multivariate analysis included ischemic time, age of donor, history of diabetes, history of hypertension and markers of acuity, including mechanical ventilation prior to transplant, pre-operative inotropic medications, and ICU admission prior to transplant. When examining 30-day and 1-year mortality, patients undergoing the biatrial technique had higher unadjusted mortality rates (6.6% vs 5.4%, p = 0.008, for 30-day mortality; 13.4% vs 11.5%, p = 0.002, for 1-year mortality). However, again, this was not significant on multivariate logistic regression (odds ratio [OR] 1.13, 95% confidence interval [CI] 0.92 to 1.41, p = 0.48, for 30-day mortality; OR 1.05, CI 0.91 to 1.23, p = 0.49, for 1-year mortality).

Table 2.

Multivariate Cox Proportional Hazards Regression Model

Risk factor	HR (95% CI)	p-valuea
Biatrial vs bicaval	1.06 (0.94–1.20)	0.31
Age	1.00 (1.0–1.01)	0.61
Gender (F vs M)	0.88 (0.77–1.01)	0.07
BMI (kg/m2)	1.00 (0.99–1.0)	0.81
Hypertension	1.18 (1.05–1.33)	0.01
Diabetes	1.20 (1.05–1.38)	0.01
Donor age	1.01 (1.01–1.02)	<0.001
HLA mismatch (HLA ≤4 vs 5 or 6)	1.06 (0.94–1.20)	0.33
Ischemic time	1.06 (1.01–1.12)	0.03
Cardiac index	0.91 (0.79–1.05)	0.20
TPG	1.01 (1.00–1.03)	0.33
PVR	0.98 (0.91–1.04)	0.50
Transplant year	1.03 (1.00–1.07)	0.15
Inotropes prior to transplant	1.16 (1.02–1.31)	0.02
Mechanical ventilation prior to transplant	2.44 (1.9–3.2)	<0.001
ICU prior to transplant	1.15 (1.01–1.31)	0.04

HR, hazard ratio; CI, confidence interval; F, female; M, male; BMI, body mass index; HLA, human leukocyte antigen; TPG, transpulmonary gradient; PVR, pulmonary vascular resistance; ICU, intensive care unit.
^a p-value based on multivariate Cox proportional hazard regression analysis, using factors significant on univariate analysis.

When survival was modeled by the Kaplan–Meier method, the bicaval group showed slightly higher rates of unadjusted survival at all time-points (p < 0.05 for each unadjusted single time-point) (Figure 2). However, the log-rank test showed no difference in overall survival during the entire study period (chi-square = 1.9, p = 0.17).

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Figure 2. Kaplan–Meier models of survival (solid line: bicaval technique; dashed line: biatrial technique). A survival table is given with number of patients at risk in parentheses. The p-value corresponds to Mantel–Cox log-rank test results (based on OPTN data, September 2006).

Other outcome variables included need for permanent pacemaker placement and total hospital LOS (both variables included in the UNOS dataset). Biatrial patients had a longer total hospital LOS and greater requirement for permanent pacemaker placement (Table 3). Both of these effects held true on multivariate, linear and logistic regression, respectively.

Table 3.

Bivariate and Multivariate Analysis of Secondary Outcome Variables

	Outcome	Biatrial (N = 6,724)	Bicaval (N = 5,207)	p-valuea
Bivariate	Permanent pacemaker placementb	343 (5.3)	103 (2.0)	<0.001
	Length of hospital stayc	20.9 (0.40)	18.8 (0.28)	<0.001
		OR or regression coefficient (95% CI)
Multivariate (biatrial vs bicaval)	Permanent pacemaker placementd	2.88 (2.10–3.94)		<0.001
	Length of hospital stayd	2.44 (1.11–3.77)		<0.001

OR, odds ratio for logistic regression; CI, confidence interval.
^a p-value for bivariate analysis is based on either chi-square (pacemaker) or Student’s t-test (LOS). p-values for multivariate analysis are based on either logistic (pacemaker) or linear (LOS) regression analysis. p < 0.05 was considered statistically significant.
^b Data expressed as
^c Data expressed as days (SEM).
^d Data expressed as OR or regression coefficient (95% CI).

Examination of center volume revealed mean annual institutional volumes ranging from 1 to 118 transplants/year. High-volume centers (defined as those performing >40 heart transplants per year) performed a greater percentage of transplants with the bicaval anastomotic technique (29% vs 20%), whereas centers performing <10 transplants per year performed a lower percentage (9% vs 16%). After adjusting for baseline characteristics, the addition of center volume in multivariate models did not affect 30-day, 1-year or cumulative mortality between techniques (OR [biatrial vs bicaval] 1.09, CI 0.74 to 1.61, p = 0.65, for 30-day mortality; OR 1.08, CI 0.82 to 1.44, p = 0.55, for 1-year mortality; hazards ratio [HR] 0.94, CI 0.76 to 1.14, p = 0.52, for cumulative mortality).

Discussion

Our analysis demonstrates that there was no difference in survival between bicaval and biatrial techniques when modeled with long-term follow-up and adjusted for confounding variables. Although the rates of mortality were higher for the biatrial group at 30 days and 1, 3 and 5 years, this represents unadjusted mortality, which disappears in both the logistic regression and proportional hazards model for all time-points.

The first surgical description of OHT with separate pulmonary and bicaval anastomoses was presented by Yacoub et al in 1989 in response to concerns over outcomes related to a biatrial anastamosis.^{[5] and [6]} The new method was used by Dreyfus et al² in 1991, and then adopted to a bicaval technique and formally described in two separate clinical series by Sievers et al⁴ and Sarsam et al.³ Although concerns exist for complications related to caval anastomoses (IVC and SVC stenoses), studies have shown a clear advantage for the bicaval technique in terms of improved peri-operative hemodynamics,¹⁵ superior atrial function,^{[7] and [8]} less tricuspid regurgitation^{[11], [12] and [13]} and decreased arrhythmias.^{[10] and [16]} Whether a survival benefit exists with the bicaval technique is less clear.

Aziz and colleagues examined mid-term survival in a retrospective cohort of 201 patients.¹⁴ The study was conducted between 1991 and 1997 and found significantly lower 1-, 3- and 5-year survival in the biatrial cohort. Blanche et al also showed decreased 1-, 2-, 3- and 4-year survival in the first 117 patients undergoing the biatrial anastomotic technique at their institution.¹⁷ Both sets of investigators cited improved hemodynamics with preservation of right ventricular function as the likely reason for improved survival. Although these studies were both well constructed, the results have not been replicated in subsequent single-institution series examining survival differences based on technique.^{[10], [15] and [18]} The fact that these early studies were conducted at single centers in the early to mid-1990s, when the bicaval technique was in its infancy, limits the applicability to modern-day practice. Furthermore, any comparison between the two techniques conducted in the 1990s has the potential for significant selection bias associated with improvements in peri-operative care and immunosuppression regimens as the majority of biatrial techniques were performed in an earlier era.

A recent randomized, controlled trial conducted by Jeevanandam and colleagues aimed specifically to measure the incidence of tricuspid regurgitation after OHT with both techniques but also examined survival differences.¹³ The investigators concluded that tricuspid regurgitation, all-cause short-term mortality and long-term cardiac-related mortality are decreased when using the bicaval anastomotic technique. Although the strengths of their study lie in its design and close follow-up, the sample size of 60 patients and the fact that it was conducted at a single institution with increased bicaval experience may limit its broad applicability.

We have attempted to mitigate the concerns of previous studies by focusing on a modern cohort within a large multi-institutional database. Our analysis has focused on the years 1999 to 2005, when an approximately equal number of biatrial and bicaval transplants were performed. Our goal was to examine all centers, not just specialized centers of expertise, to determine whether a true difference in survival exists between techniques.

It is noteworthy that institutional volume did not appear to affect outcomes with the two techniques. No center volume (including very low volume centers, <10/year) showed significant differences in mortality rates between techniques. Thus, although high-volume centers do perform proportionately more transplants with the bicaval technique, increased experience with either technique does not appear to lead to a survival benefit.

The bicaval technique did improve secondary outcomes. Namely, need for permanent pacemaker placement and length of hospital stay was significantly lower in the bicaval group. Although a decreased requirement for permanent pacing (related to sparing of the sinus node) has been reported in the literature,^{[10] and [18]} a recent report by Zieroth and colleagues showed that this may not be the case in the modern era with the use of extended donors.¹⁹ Our findings, however, support the notion that permanent pacing requirements are lower in those patients who undergo OHT with bicaval anastomoses. In addition, decreased length of stay with the bicaval technique has been reported in the literature¹⁵ and it is likely that these two effects are interconnected as patients with greater rates of arrhythmias and increased requirements for pacing frequently suffer from prolonged hospitalization. It is also noteworthy that no difference in ischemia time was observed when using the bicaval technique. This concern, which has been raised by proponents of the biatrial anastomotic technique, does not appear to hold true when examining this large sample.

Limitations

We recognize that there are several limitations in our investigation. First, our study is retrospective and cannot account for inherent undocumented differences in patient characteristics. Although we attempted to control for selection bias with multivariate statistical methods, we concede that a fundamental problem of any retrospective study examining outcomes is a lack of control of all potential confounders. Second, nationwide administrative clinical registries, including the one we used, and studies based on them, are reliant on accurate coding of information. We acknowledge that the data presented herein were not necessarily entered by individuals with clinical expertise. However, although errors and variance in the data undoubtedly exist, we have assumed that these are randomly distributed and should not lead to a significant bias in our conclusions. Third, by using a nationwide sample we are dependent on the variables and definitions present in the data set. In many circumstances, we would have chosen to include additional variables that were not part of our control. Specifically, the UNOS database offers no mention of post-operative arrhythmias, atrial function or valvular insufficiency—outcome variables that would have been of interest. This and additional variables (including post-operative hemodynamics) would have added strength to the study.

We have been able to provide an unbiased look at outcomes after anastomotic techniques in heart transplantation using an extremely large sample. Without a randomized, controlled clinical trial, we believe that a retrospective study of a nationwide sample with compensatory statistical methodology constitutes a reasonable approach to addressing these issues.

Our Approach

At our institution, we continue to favor the bicaval anastomotic technique. We believe that early post-operative hemodynamics are improved and we are encouraged by the decreased requirements for permanent pacing. In light of this study, and the many patients who have undergone the biatrial technique at our institution and others, however, we are comforted to know that there does not appear to be a difference in short- or mid-term survival between these techniques.

The current study is the single largest series examining bicaval vs biatrial anastomotic techniques for OHT. We found no difference in survival between the two groups, although the bicaval technique was found to be associated with shorter LOS and pacemaker placement. In the modern era of heart transplantation, biatrial anastomosis continues to offer survival comparable to that of bicaval anastomosis.

References

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6 N.R. Banner, A. Khaghani and M. Fitzgerald et al., The expanding role of cardiac transplantation. In: R. Unger, Editor, Assisted circulation III, Springer, Berlin (1989) 487–467.

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18 N.A. Solomon, J. McGiven and X.Z. Chen et al., Biatrial or bicaval technique for orthotopic heart transplantation: which is better, Heart Lung Circ 13 (2004), pp. 389–394. SummaryPlus | Full Text + Links | PDF (118 K)

19 S. Zieroth, H. Ross and V. Rao et al., Permanent pacing after cardiac transplantation in the era of extended donors, J Heart Lung Transplant 25 (2006), pp. 1142–1147. SummaryPlus | Full Text + Links | PDF (143 K) | View Record in Scopus | Cited By in Scopus (2)

Supported in part by the Health Resources and Services Administration, Contract No. 234-2005-370011C.

The content of this article is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government.
Reprint requests: Ashish S. Shah, MD, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 North Wolfe Street, Baltimore, MD 21287. Telephone: 410-955-2800. Fax: 410-955-3809.