Table VIII-1. Factors That Independently Influence Survival After Heart Transplantation

Risk Factor for Death	P-values
	Early Phase	Constant Phase
Recipient Variables
Age (older)	.003	.001
Age (younger)		<.001
Black race		<.0001
Obese recipient	.002
Cachetic recipient	.005
Congenital Heart Disease	.002
Non-congenital etiology		.04
Previous sternotomy	<.0001
> 1 previous sternotomy	.03
Herpes - negative	.02
Hx of cocaine use		.004
Hx of cigarette use within 6 mos of transplant		.0002
Hx of pulmonary disease	.05
Hx of insulin-dependent diabetes		.0001
Hx of peripheral vascular disease		.03
Panel (Percent) Reactive Antibody > 10	<.0001
Creatinine clearance at listing (lower)	.0005
Higher serum creatinine at tx	<.0001
Higher difference between systolic PA and PCWP (PA-PCWP, TPG)	.0003
Higher right atrial mean pressure	.003
On Ventilator at transplant	<.0001
Intra Aortic Balloon Pump at transplant	.02
VAD, 14 days or less	.003
Days on VAD	.04
Earlier date of transplant		<.0001
Donor Variables:
Female	.0001
Male		0.02
Age (older)	<.0001	<.0001
Longer myocardial ischemic time	<.0001
Donor smaller BMI than recipient	.008

LUNG

Lung Waiting List Characteristics

Lung transplantation continues to be accepted as a viable therapeutic intervention for patients with end-stage lung disease, as evidenced by an ever-expanding waiting list. The lung transplant waiting list reached a new high of 3,836 registrants as of December 31, 2003 [Table 12.1]. This growth reflects a small (3%) increase over 2002 and a 2.4-fold increase from 1994. Despite the continued growth in the number of new registrants, the number of transplants performed remained relatively constant at around 1,000 transplants per year for the past three years (Figure VIII-9) [Table 12.4a]. It is important to note that over the past five years (1999 to 2003), the number of active patients at year-end stabilized between about 2,300 and 2,500, while the percentage of active patients continued to decline, reaching a new nine-year low of 61% [Table 12.1]. The number of new registrations increased from 1,889 last year to 1,954, thus maintaining a volume of nearly 2,000 registrants per year for the past seven years [Table 12.2].

Despite the relatively constant number of registrants for the past seven years, the number of inactive patients has nearly doubled since 1998 (Figure VIII-10) [Table 12.1]. The increase in the number of inactive patients likely reflects an increasingly common practice of early placement on the waiting list. Because waiting times are currently extremely long in the United States, and because the priority system is currently based on accrued waiting list time (though this is scheduled to change in the near future, as explained at the end of this chapter), many centers have turned to the practice of listing patients early in the course of their disease in order to increase priority, predicting the high likelihood of disease progression over time. This is done knowing that patients who have accrued a substantial amount of waiting time are more likely to receive an organ. Within the framework of the current allocation system, remaining inactive on the waiting list (rather than being de-listed) allows previously accrued active time to be retained. This has given those patients with relatively stable and predictable disease a greater chance of getting an organ, since the priority for receiving a lung transplant is based on the amount of accrued active waiting list time (assuming geographical proximity and blood type compatibility). Consequently, stable patients who move to the top of a center's waiting list with a substantial amount of accrued waiting time can be placed on an inactive status until they become sick enough to warrant the risk of transplantation. Although early wait-listing is advantageous for those with a stable course, there is a major disadvantage to this system for patients with rapidly progressive illness or for those who are referred too late in the course of their disease.

The age of new registrants continues to increase, with the percentage of candidates on the waiting list at the end of the year older than 50 years increasing from 39% in 1994 to over 50% in 2003 (Figure VIII-11) [Table 12.1]. The percentage of African American patients on the lung waiting list increased from 8% in 1994 to 10% in 2003; the percentage of Hispanic/Latino registrants rose from 4.8% to 5.1% over the same period. Waiting list registrants were most commonly female (58%), older than 50 years of age (52%), white (88%), blood type O (48%), US residents (99%), and awaiting their first transplant (97%) [Table 12.1]. Approximately 64% of registrants had been waiting more than a year for an available organ, and 44% of registrants had been waiting for more than two years (these waiting times include periods of inactive waiting list status) [Table 12.1]. These waiting time statistics are increasingly a concern for those patients with diseases that have an unpredictable and rapidly deteriorating course, such as idiopathic pulmonary fibrosis (IPF).

While the period of time to transplant had been increasing between 1994 and 1999, there has been a change in this pattern, as shown in Figure VIII-12. In 1999, 25% of recipients were transplanted within 451 days of listing, but in 2003 this same percentage of recipients received transplants within 247 days of listing [Table 12.2]. Offsetting the general trend toward longer average times to transplant is a decrease in annual death rates on the waiting list, as shown in Figure VIII-13. There has been a decrease from 224 deaths per 1,000 patient years at risk in 1994 to a 10-year low of 130 in 2003 [Table 12.3]. While this may be secondary in part to improvement in care for end-stage lung patients, it is also likely a result of lower-acuity patients on the waiting list yielding a decreased death rate. Therefore, the observation of a change in average waiting list mortality over time should be viewed with uncertainty.

The waiting time for lung transplantation remains extremely long in the US, with a median waiting time for the 50th percentile of just over three years (last assessed in 1998 due to insufficient current data) and the 25th percentile at over 200 days in 2003 (Figure VIII-12) [Table 12.2]. There are, however, some differences in waiting time based on age as of 2003, with patients between the ages of 18 and 49 waiting more than 363 days while older patients waited shorter times (25% of candidates age 50-64 being transplanted within 225 days and 25% of candidates 65 and older being transplanted in 101 days) [Table 12.2]. Whether this is due to more liberal donor criteria for older recipients is unclear. Annual death rates per 1,000 patient years on the lung waiting list in 2003 were relatively low for patients aged 11-17 years (165), 18-34 years (129), 35-49 years (117), and 50-64 years (131) [Table 12.3]. There was a marked drop in annual death rate for the 1-5 year age group from a high of 983 per 1,000 patient years at risk in 1998 to 61 per 1000 patient years at risk in 2003; however, the data need to be interpreted with caution because of the small number of patients represented by this group (n=38 and 25 in 1998 and 2003, respectively).

There have been approximately 10%-20% more women than men on the waiting list over the past decade, which may contribute to the longer observed time to transplant for women [Tables 12.1 and 12.2]. Despite the longer average waiting time for women, in most years annual death rates per 1,000 patient years at risk on the waiting list were slightly higher for men than for women [Table 12.3]. In 2003, men experienced a death rate of 141 deaths per 1,000 patient years at risk versus a death rate of 121 per 1,000 patient years at risk among women. The explanation for these apparently discordant statistics may be secondary to a higher representation of diseases with an increased likelihood of death on the waiting list for men compared to women. Alternatively, the difference in survival could be explained by gender differences in the course of the underlying disease.

Lung Transplant Recipient Characteristics

Over the last 10 years, the total number of lung transplants slowly increased from 723 transplants performed in 1994 to 1,085 in 2003 [Tables 12.4a, 12.4b]. Despite this overall increase, the numbers for the last three years have hovered at slightly over 1,000 transplants per year. This leveling is most likely secondary to the relatively small increase in the total number of lung donors, combined with an increasing percentage of double lung transplants being performed. Older patients account for the majority of transplant recipients, with the largest cohort, those 50-64 years old, representing nearly 57% [Table 12.4a]. As has been the case through the last 10 years, most recipients (>90%) were white. Gender distribution over the years has been relatively equivalent, with minimal variations [Table 12.4a]. In view of the higher proportion of women on the waiting list, it is not obvious why such a discrepancy exists. Potential explanations include smaller recipient size, with fewer small donors and a reluctance to transplant oversized lungs; differences in gender distribution within each of the pretransplant diagnoses; and differences in the waiting time for those diagnoses and improvements in medical care.

The major primary diagnoses and percentages for the 2003 deceased donor recipient cohort were as follows: emphysema (40%), IPF (22%), cystic fibrosis (16%), alpha-1-antitrypsin deficiency (6%), and primary pulmonary hypertension (PPH, 4%) [Table 12.4a]. The percentage of transplants for emphysema was the same as for 2002 which, overall, represented a marked decrease compared to 2000 percentage of 44%, while most of the other diagnostic groups had commensurate small increases since 2001 (Figure VIII-14). Furthermore, 97% of lung recipients had not undergone any previous solid organ transplant. The majority of recipients were not hospitalized at the time of transplantation, and only 5% of patients were on life support when transplanted. In comparison with 1994, when more than 60% of lung transplant procedures involved single lung transplantation, the period from 1995 through 2001 shows an increasing use of double lung transplantation, with the data from 2003 again showing more double lung transplants performed than single lung transplants as in 2002 (Figure VIII-15). This trend likely reflects the sentiment among lung transplant teams that long-term morbidity and mortality are less with double lung transplants than with single lungs. While there have been retrospective analyses showing an improved intermediate and long-term survival for double lung recipients with chronic obstructive pulmonary disease (COPD), this finding has not been shown for other underlying diseases and these comparisons have not adjusted for potentially significant confounding variables, such as age and other factors (6).

Immunosuppression for lung transplantation continues to be predominantly a triple-based regimen using corticosteroids, a calcineurin inhibitor, and an antimetabolite. The relative use of the two main drugs in each of the latter two categories have recently changed, in 2003 showing a predominance of tacrolimus at 66% and mycophenolate mofetil at 45% [Table 12.6b]. This contrasts sharply with 1998, when both cyclosporine (particularly Neoral) and azathioprine were utilized as the major immunosuppressive regimen at 73% and 70%, respectively. Interestingly, more lung recipients now receive induction therapy (44%) compared to five years ago, when only 23% received such therapy [Table 12.6a]. For those receiving induction therapy there is now less use of cytolytic therapies such as anti-lymphocyte globulins or OKT3 and much greater use of interleukin-2 receptor antagonists.

Lung Transplant Outcomes

Previous SRTR reports did not demonstrate a significant improvement in short- or long-term outcomes following lung transplantation in recent years. These data are consistent with international data from the International Society for Heart & Lung Transplantation (ISHLT) Registry, which have not demonstrated a difference in overall survival following lung transplantation when analyzed by era (1993-1997 versus 1998-2001) (6). However, the current analysis of SRTR unadjusted survival data (as well as adjusted survival, data not shown) for the most recent patient cohort (2002) demonstrates that one-year survival was statistically significantly better for patients transplanted in 2002 than for patients transplanted in 2001 (82% versus 78%, p=0.048) as well as better than previous years (82% for the 2002 cohort versus 76% for the 1994 cohort, p=0.004) (Figure VIII-16) [Table 12.13a]. Additionally, three-month survival was statistically significantly better for the 2002 cohort compared to the 1994 cohort (90% versus 87%, p=0.03); however, it was not significantly different compared to the 2001 cohort (90% versus 89%, p=0.33). Five-year survival, however, has remained disappointing at levels of approximately 45%, although the most recent cohort with sufficient elapsed time from transplant for analysis is the 1998 cohort. Graft survival rates have been only slightly lower than patient survival rates, given the relatively low rate of re-transplantation (2%-4% of lung transplants over the last 10 years and 3% of lung transplants in 2002) [Table 12.4a]. It remains to be determined whether these improved short-term outcomes are simply an aberration, the result of slight alterations in recipient demographics, or reflections of other improvements, such as better donor management and enhancements in postoperative management; analyses of future outcomes will be required. A greater understanding might also be achieved through more rigorous analysis of the variables than possible in the scope of this chapter.

The outcomes reported in this chapter describe 30-day and one-year survival for patients transplanted during 2001-2002 and five-year survival for patients transplanted during 1997-1998. Analysis of patient survival (unadjusted survival) by recipient demographic variables reveals findings similar to the 2003 report. Conclusions based on this analysis are limited as a multivariate analysis addressing confounding variables was not performed. As described in the 2003 report, ethnicity (Hispanic/Latino versus Non-Hispanic/Non-Latino), gender, and blood type had no effect on survival. Race, however, had a notable impact on five-year outcomes, although there was no difference in one-year survival. Five-year survival in whites was 47% versus 35% in African Americans, a statistically significant difference [Table 12.12a]. Five-year survival in Asians was 58% but was not significantly different from Caucasians or African Americans due to the small number of recipients (n=12) and the large standard error. Obvious confounding covariates that could affect these outcomes could be primary disease or HLA disparity leading to late mortality as well as other potential factors. Further analyses may help to clarify the etiology of this discrepancy and lead to improved outcomes. As expected, the acuity of illness of the recipient at the time of transplant had a significant impact on survival. Survival for patients in an intensive care unit (ICU) at the time of transplant was worse than for patients who were out of the hospital prior to transplant, although this difference was statistically significant only at three months (79% versus 90%, p=0.04) [Table 12.12a]. Similarly, the need for life support at the time of transplant resulted in lower survival at all three time points, although this difference too was statistically significant only at three months (80% versus 90%, p=0.02). It is notable that in this data set, the reason for ICU stay or the type of life support required is not defined. ISHLT Registry data identifies ventilator requirement, one of the more likely events in lung transplant candidates leading to ICU admission, at the time of lung transplant as a risk factor for one-year mortality with an odds ratio of 2.42 (6). Similarly, data from Eurotransplant identifies ventilator support at the time of transplant as a risk factor for one-year mortality with an odds ratio of 1.59 (7). However, several groups have reported good short-term outcomes in small series of selected patients who underwent transplantation after long-term, stable ventilator dependency (8, 9) or after both short- and long-term mechanical ventilation (10). Further investigation may help to clarify the risk as well as other confounding variables that may affect outcome under these conditions and lead to an improved balance of equity and utility.

As in the 2003 report, aside from the <1 year age group (which had only 5 recipients), the lowest three-month survival was seen in the 11-17 year old group (83%); the lowest five-year survival was seen in the 6-10 year old group (19%), although the number of recipients was small (n=16) [Table 12.12a]. Of adult recipients (318 years), there was no statistical difference in one-year survival between the 18-34, 35-49, 50-64 and 365 year old groups. Five-year survival, however, was statistically significantly poorer in the 365 year old group compared to the 18-34 year old group (34% versus 50%, p=0.01) and compared to the 35-49 year old group (34% versus 53%, p=0.003), while there was a trend toward worse survival compared to the 50-64 year old group (34% versus 43%, p=0.12) [Table 12.12a]. Analyzed as a continuous variable, ISHLT Registry data also suggests an effect of recipient age on survival (6). However, in contradistinction to the current data, ISHLT data suggest a negative effect on both one- and five-year survival. Intuitively, the worse outcome in the elderly may be due to rising all-cause mortality or simply the greater effect of immunosuppression-related toxicities in this patient population. An analysis of these factors may enhance outcomes in this patient population, especially with increases in understanding of the senescent immune system and an improved ability to tailor immunosuppression to individual needs.

Patient survival stratified by primary diagnosis was similar to that of previous reports and consistent with ISHLT Registry data (6) and Eurotransplant data (7). Aside from the few patients with congenital heart disease (n=29), five-year survival was worst for patients transplanted for IPF (39%, p<0.05 compared to emphysema, cystic fibrosis or alpha-1-antitrypsin deficiency) and PPH (43%) while the best survival was achieved for cystic fibrosis (50%), alpha-1-antitrypsin deficiency (49%) and emphysema (47%) [Table 12.12a]. Similarly, one-year survival was worst for IPF (75%) and PPH (72%) while it was best for emphysema (84%) and cystic fibrosis (82%). Both ISHLT and Eurotransplant data have found PPH and IPF to be risk factors for one-year mortality, with odds ratios for PPH of 2.74 and 2.84, respectively, and odds ratios for IPF of 1.91 and 1.70, respectively (7, 8). In the 2003 report, retransplantation, along with transplantation for PPH and congenital heart disease, were noted to result in the worst five-year survival. In the current analysis, retransplantation was not considered separately but was included in the category "other," which had a 47% five-year survival. However, it is notable that in the most recent analysis of ISHLT registry data, retransplantation remained a risk factor for one-year mortality with an odds ratio of 2.03 but it was not an independent risk factor for five-year mortality (6).

Given the wide discrepancy discussed above between the number of lung transplants performed on a yearly basis and the number of patients waiting for a transplant, much attention has been drawn toward donor utilization and, in particular, the suitability of donor organs for transplantation. In the current data set, two variables of interest can be examined: cold ischemia time and donor age. Much attention has focused on these variables as perceived limitations in acceptable cold storage times may limit geographic distribution of organs while unacceptable outcomes with aged donors will limit their use. We examined the effect of cold ischemia time on graft survival using OPTN/SRTR data. It has been suggested that cold ischemia times in excess of 6 hours do not adversely affect short or long-term survival (11). The data analyzed here support this thesis (Figure VIII-17). There was no detrimental impact of cold ischemia times in excess of 8 hours on one- or five-year graft survival rates [Table 12.9a]. In fact, cold ischemia times in excess of 8 hours paradoxically resulted in greater five-year survival compared to ischemia times of 1.5 - 3 hours, 3 - 4.5 hours and 6 - 8 hours [Table 12.9a]. It is likely that other covariates played a role in enhancing survival in this group (e.g., recipient diagnosis). A diminished one-year survival rate was seen with cold ischemic times of 0 - 1.5 hours, but the number of patients in this cohort was small (n=24) [Table 12.9a].

In recent years, much attention has been focused on the relationship of higher patient volume to outcomes in health care (12). In the field of transplantation, several studies have reported better outcomes at higher-volume centers for certain types of organ transplants including pediatric renal (13), liver (14, 15), kidney (15) and cardiac transplantation (16). Other studies have failed to demonstrate this effect (17). Despite the relatively high mortality following lung transplantation compared to transplantation for other solid organs, data regarding center volume effect are scarce. A recent analysis of Eurotransplant outcomes did not demonstrate an effect of center volume on one-year survival following lung transplantation (7). The SRTR has analyzed the univariate effect of center volume on graft survival. Centers were divided by average volume over the analysis period into low volume (1-20 lung transplants per year), moderate volume (21-40 lung transplants per year) and high volume (>41 lung transplants per year). For the one-year survival analysis (2001-2002 cohort, total number of lung transplants = 2,062), 761 transplants (37%) were performed by low-volume centers, 891 (43%) by moderate-volume centers and 410 (20%) by high-volume centers. For the five-year survival analysis (1997-1998 cohort, total number of lung transplants = 1,745), 50% of transplants were performed by low-volume centers, 34% by moderate-volume centers and 16% by high-volume centers. Five-year survival was statistically significantly better for high-volume than low-volume centers and one- year survival was statistically significantly better for both moderate-volume and high-volume centers when compared to low-volume centers (Figure VIII-18). A similar relationship was present at three months following transplantation (data not shown) demonstrating a difference in early outcomes as well. However, the effect was greatest at five years, with a survival difference of 9% for high-volume versus low-volume centers (51% versus 42%). There was no difference in survival between moderate- and large-volume centers. This univariate analysis is certainly limited by potential confounding variables (e.g., distribution of recipient diagnoses) and a multivariate analysis should be performed. If this relationship holds true in multivariate analysis, variables that differ between centers with different transplantation volumes should be further examined. Such an analysis could lead to process improvement and enhanced survival at centers with lesser outcomes.

Heart-Lung

Heart-Lung Waiting List Characteristics and Outcomes

The total number of patients awaiting heart-lung transplants has continued to decline from a high of 250 in 1998 to 189 in 2003, with only 106 of the 189 (56%) being active on the waiting list [Table 13.1]. The number of new listings each year has also fallen steadily, dropping from 130-160 in 1994-1998 to only 69 new listings during 2003 [Table 13.2]. While in 2003, 48% of registrants on the heart-lung waiting list were younger than 35 years old, the average age of registrants has been rising over time. At the end of 2003, nearly 20% were over the age of 50 [Table 13.1], often considered the upper age limit for combined heart-lung transplant. Congenital heart disease remains the most common indication for listing (38%), followed by PPH (19%), other heart/lung diseases (11%), and cystic fibrosis (2%). However, the listing indication remains unknown in 30% of cases in the registry, up from approximately 18% in 1995-1998 [Table 13.1].

The decline in the number of patients actively awaiting heart-lung transplant has led to shorter waiting list times. The 25th percentile of time to transplant for new registrants fell from a high of over two years (792 days) in 1997 to less than a year (292 days) in 2003 [Table 13.2]. The annual death rate per 1,000 patient years at risk on the waiting list has also gradually declined, dropping from approximately 250 in 1996-1997 to approximately 200 in 2001-2002 and around 100 in 2003 [Table 13.3]. The low waiting list mortality rate for 2003 may reflect incomplete data reporting. Subgroup analysis is difficult due to the small numbers of such candidates, but there do not appear to be major differences in waiting list mortality with respect to gender, race, ethnicity, or blood group. However, younger patients appear to have higher waiting list mortality than older patients [Table 13.3], possibly reflecting differences in waiting list mortality for congenital heart disease compared with PPH.

Heart-Lung Transplant Recipient Characteristics

Only 29 heart-lung transplants were performed in 2003. The volume of heart-lung transplants seems to have stabilized at about 30 transplants per year, down from about 70 in 1994-1995 [Table 13.4]. Only five centers performed more than one heart-lung transplant in 2003; only one performed more than three procedures [Table 13.15]. The relative distribution of gender, age, racial, and ethnic characteristics remains fairly stable, closely following the characteristics of patients listed for heart-lung transplant. In 2003, approximately 60% of heart-lung recipients were female, 21% were pediatric (younger than 18), 55% were over the age of 35, 14% were non-white, and 17% were Hispanic/Latino [Table 13.4]. Candidates with blood group O appear to be transplanted at a lower rate (28% of transplants) than would be expected by the proportion of listings (53% of registrants) [Tables 13.4, 13.1]. However, the mortality rate on the waiting list for type O listings does not appear to be significantly higher than for other blood groups [Table 13.3], probably reflecting a tendency for centers to list blood type O patients at an earlier stage in the course of their disease. The proportion of recipients on life support at the time of transplant has gradually risen from 10% in 1994 to 45-50% in 2002-2003 [Table 13.4]. This compares with 75% of heart recipients either Status 1A or 1B at the time of transplant [Table 11.4], but only 5% of isolated lung transplants on life support at the time of transplant [Table 12.4a].

Heart/Lung Patient and Graft Survival

Unfortunately, the outcomes of combined heart and lung transplant have not improved much over the past decade. The actual unadjusted patient survival has remained about 60% at one year (range 56%-78%), 45% at three years (range 38%-62%), and only 40% at five years (range 35%-54%) [Table 13.13]. Interestingly, the survival appears to be better for recipients age 35 and older than for those under 35 [Table 13.11]. This may reflect the higher risk of heart-lung transplant for younger recipients with congenital heart disease when compared to older recipients with PPH.

The adjusted patient survival rate for heart-lung transplant is 75% at three months, 68% at one year, 46% at three years, and only 38% at five years [Table 13.11]. These outcomes are consistently worse than the corresponding adjusted patient survival rates for isolated lung transplants (90%, 80%, 61%, and 46% respectively) [Table 12.11a]. This difference is largely due to the worse outcomes following heart-lung transplant for congenital heart disease (62%, 62%, 51%, and 31% respectively) [Table 13.11]. For PPH, the adjusted patient survival rates are actually better after combined heart-lung transplant than after isolated lung transplant (80%, 75%, 55%, and 49% versus 74%, 70%, 54%, and 39% respectively) [Tables 13.11 and 12.11a]. Unfortunately, the small numbers of heart-lung transplants do not permit extensive analysis of subgroups. However, there is a trend toward improved early adjusted patient survival for females and older recipients. Although the numbers are very small, children younger than ten years old appear to have a very poor (less than 20%) survival at one year and beyond [Tables 13.11 and 13.12], raising questions of utility in this age group.

Heart/Lung Death Rates

The first-year posttransplant annual death rate per 1,000 patient years at risk fell from a high of 636 in 1997 to 572 in 2002, the last year with adequate follow-up [Table 13.7]. As with waiting list and graft survival analysis, subgroup analysis is limited by the small numbers of heart-lung transplant recipients, which also prevent multivariate analysis. However, first-year posttransplant mortality rate tends to be higher for recipients on life support at transplant, male recipients, older adults recipients, and recipients of older donors. There are not enough data to examine trends in first-year posttransplant mortality rates based on race, ethnicity, or blood type [Table 13.7].

Prevalence of People Living with Functioning Transplant

The prevalence of heart-lung recipients has remained fairly constant at 230-250 over the past decade, differing from the prevalence of people living with functioning transplants of other organs after one year, which has increased [Table 13.14]. This constant prevalence indicates that number of patients receiving a transplant each year is about equal to the number dying or developing graft failure. The small numbers make subgroup analyses difficult, but 60% are female, 93% are white, 5% are African American, 98% are US residents, and only 13% are children.

 

Recent Developments In Deceased Donor Lung Allocation Policy In The United States

A far-reaching change in allocation policy for deceased donor lungs occurred just as this chapter was being prepared. From a distribution system based solely on waiting time, the pulmonary transplant community has moved in one large step to an algorithm based upon the concept of transplant benefit as the principal arbiter of lung allocation.

The current policy, in effect since June 1990, offers lungs first to candidates within the OPO where the donor is hospitalized based on active waiting time, then to candidates listed at transplant centers within concentric circles increasing in increments of 500 nautical miles. The only major modification to this policy occurred in March 1995, from which time credit for 90 days of waiting time was assigned to patients with IPF at the time of listing, in recognition of the more rapid deterioration of these patients while on the waiting list.

The new allocation policy, approved by the Board of Directors of the Organ Procurement and Transplantation Network (OPTN) in June 2004, is in part a response to the 1999 Final Rule for operation of the OPTN. The mandate for the OPTN is to achieve the best use of donated organs by directing them to those most in need, while not offering them to individuals too sick to survive the operation or otherwise derive benefit (18). In addition, the Final Rule required policies based on sound medical judgment and that seek to achieve the best use of organs. Although the initial debate focused on liver distribution, the Final Rule required the OPTN to examine all organ distribution algorithms and either demonstrate that they satisfied the principles espoused or alter the algorithms to address the new philosophy.

Aside from the provisions of the Final Rule, it was increasingly recognized that allocation by waiting time would never be able to adequately account for the random times in the course of disease during which patients present for evaluation for lung transplantation. Thus, patients who presented early were offered a place on the waiting list, knowing that they would not be offered an organ very soon, and hoping that they would be judged in need of a transplant once they reached the top of the list. Conversely, patients who presented late in the course of disease or whose disease progressed more rapidly than the average patient on the waiting list would have no recourse to more expeditious transplantation. This led to a confusing picture in which many candidates were eventually placed on inactive status on the list (Figure VIII-10) (19). Others died without opportunity for transplant (Figure VIII-19). Paradoxically, those who could survive the longest on the waiting list (principally those with COPD) had a better chance of being offered a donor lung, even though many COPD patients do not appear to have a survival benefit from the transplant (20).

The new allocation system is intended to maximize the survival benefit of lung transplant by incorporating a prediction of the difference between measures of waiting list survival and posttransplant survival for each candidate (21). An additional goal is to minimize deaths on the waiting list by balancing the benefit calculation and the degree of medical urgency, as embodied in the waiting list survival measure. The clinical and statistical foundations underlying these determinations are outlined below.

Separate Cox regression models were fitted for waiting list candidates and transplant recipients age 12 and older. Over 30 clinical and demographic variables collected at the time of listing were included in the model. Patients were censored at the time of transplant in the waiting list mortality model. Four main categories of diagnosis were found to be strongly associated with waiting list and with posttransplant mortality (22-26). These include Group A: obstructive lung diseases, typified by chronic obstructive pulmonary disease; Group B: pulmonary vascular diseases, principally primary pulmonary hypertension; Group C: cystic fibrosis; and Group D: restrictive lung diseases, mainly IPF. About 20% of candidates and recipients have diagnoses other than the four mentioned, and these were assigned into one of the four groups using a combination of pathophysiologic similarity and comparability of mortality risk (Table VIII-2). A number of other factors were significant, some of which varied significantly by diagnosis group, and appropriate statistical terms were included for these covariates (Table VIII-3) (22-26).

Group E is reserved for patients under the age of 12, irrespective of diagnosis. Analyses of pediatric candidates and recipients demonstrated that adolescent mortality risk was very similar to that for adults. Predictive factors for mortality in younger children have not yet been fully worked out. Thus, allocation of donor lungs for these patients will continue to be based on waiting time.

A number of factors identified as statistically significant were judged by the OPTN Lung Allocation Subcommittee to be inappropriate to be incorporated into the organ distribution algorithm because they were too subjective to be applied consistently. An example is the use of modest daily doses of prednisone for Group A patients, which was associated with an increased risk of death on the waiting list. Factors like these were eliminated from the models but had little effect on the other variables that were judged appropriate for inclusion in the algorithm.

Based on individual patient risk factors and associated hazard ratios for death on the waiting list and following transplantation, the Subcommittee then considered options for summarizing the comparison of each patient's risk of death on the waiting list over the subsequent year to their risk of death during this same period if transplanted. One-year survival estimates provided by the Cox models were considered, as well as estimates of the length of time each patient would live during the next year with or without transplant. This latter set of summary measures, referred to as one-year expected lifetimes, is calculated for each individual at the time a donor organ is being considered by summing the area under the patient's one-year Cox model estimated survival curves. Thus, for each patient, the number of days of life saved with transplant, referred to as the transplant benefit measure, is calculated as the difference between the days of life a patient would be expected to live over the next year if transplanted minus the days of life a patient would be expected to live if maintained on the waiting list over the coming year (27).

Values of one-year transplant benefit can be used to rank order patients on the waiting list. Comparisons of rankings of patients by transplant benefit according to one-year versus two-year projected lifetimes yields almost identical results. One-year values were ultimately selected in order to allow for use of the most recent data. Careful examination of rankings by transplant benefit showed that some patients who would have received a fairly high-level benefit might not have the requisite expected lifetime on the waiting list to survive until a donated lung became available. In order to better accommodate such patients, the Subcommittee recommended and the OPTN Board of Directors approved a final allocation system that balances the transplant benefit with the expected days of waiting list life during the subsequent year (an urgency measure). This balanced system results in some reordering of patients, but still results in a near maximization of overall net benefit across all patients. Thus, ranking of patients is by an allocation score calculated as the difference between the transplant benefit measure and the waiting list (urgency) measure. Mathematically, the value of this raw allocation score can range from -730 to +365. To facilitate understanding, the raw allocation score is normalized to a scale from 0 to 100 and is referred to as the Lung Allocation Score.

Equity of access to donated organs was an important consideration during the development of the Lung Allocation Score. The lung waiting list on January 1, 2003 was examined to see whether the distribution of Lung Allocation Scores would provide access to the range of candidates with a variety of characteristics. Age, gender, race, and underlying diagnosis were studied and a high level of overlap in the distribution of Lung Allocation Scores was observed among all subgroups of these candidate variables, suggesting that individuals in all subgroups will have access to donated lungs under the new system (Figure VIII-20).

The new allocation system is a work in progress. Central to the new algorithm is a plan to regularly review the predictive models for waiting list and posttransplant mortality and to update them as needed. It is anticipated that serial clinical data will be useful to identify new factors that should be incorporated into the distribution algorithm and that serially collected patient data may affect the import of factors identified as significant in the analyses. Indeed, it is the recommendation of the Lung Allocation Subcommittee that analyses be undertaken to identify factors and modify their hazard ratios in the algorithm at least every six months. Thus, as patients are transplanted and removed from the list and new patients are added, risk is assessed using the most recent cohort of patients.

Equally important is a provision for the updating of candidate data while on the waiting list. One of the deficiencies of the initial implementation is the use of baseline candidate data obtained at the time of placement on the waiting list. Until now, no updating of patient data was possible, and it is obvious that the values of important predictors of mortality are likely to change over time in concert with progression of the patient's underlying pulmonary disorder. Transplant programs will be required to update values used in the calculation of the Lung Allocation Score at least once every six months while the patient is active on the lung transplant waiting list. More frequent updates will be allowed at the discretion of the listing program.

In order to "jump-start" this process, a retrospective audit of serial candidate data has been performed from dozens of lung transplant centers around the country. Analysis of these data is now under way to determine if the risk factors and their calculated hazard ratios are appropriate and may provide important insights into the likely effects of serial data availability on the predictive models in the future.

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CONTRIBUTORS

The following individuals prepared this chapter: Mark L. Barr, MD¹; Robert C. Bourge, MD²; Jonathan B. Orens, MD³; Kenneth R. McCurry, MD⁴; W. Steves Ring, MD⁵; Tempie E. Hulbert-Shearon, MS⁶; Robert M. Merion, MD⁶. University of Southern California Keck School of Medicine and Childrens Hospital Los Angeles; ²University of Alabama, at Birmingham; ³The Johns Hopkins Hospital; ⁴University of Pittsburgh School of Medicine; ⁵UT Southwestern Medical Center; ⁶Scientific Registry of Transplant Recipients / University of Michigan.