Author + information
- Wayne C. Levy, MD⁎ ( and )
- Todd Dardas, MD, MS
- ↵⁎Reprint requests and correspondence:
Dr. Wayne C. Levy, Division of Cardiology, University of Washington, Box 356422, 1959 NE Pacific Street, Seattle, Washington 98195
Survival after cardiac transplantation continues to improve, and many transplant recipients are able to re-enter the workforce. The 2010 ISHLT report identifies the median survival among heart transplant recipients as 13 years for those patients living beyond the first year of transplant and 10 years overall (1). Functional status among transplant recipients remains relatively good, with 90% of patients having a Karnofsky Index of 80% or more and 50% of working-age recipients re-entering the workforce (1). Although transplantation remains an excellent option for those with advanced heart failure, improving both short- and long-term survival and quality of life remains an important goal.
In this issue of the Journal, Patlolla et al. (2) analyze the effect of pre-transplantation symptomatic cerebrovascular disease (sCVD) on post-transplantation mortality, morbidity, and functional status. Their analysis included all heart recipients at least 40 years of age from 1994 to 2006. sCVD was recorded by the listing center and included events before and during transplantation registration. The unadjusted rates of post-transplantation stroke (4.0% vs. 1.4%, p < 0.001) and mortality (8.9% vs. 7.4%) were higher among patients with pre-transplantation sCVD. The increased risk of stroke was preserved after multivariate adjustment (hazard ratio [HR]: 2.41; 95% confidence interval [CI]: 2.02 to 2.87), although the association between death and sCVD was not preserved after adjusting for other factors (HR: 1.08; 95% CI: 0.98 to 1.2). The occurrence of functional decline, defined as a Karnofsky Index score <80% at all successive follow-up visits, was higher for those with sCVD (annualized incidence 3.7% vs. 3.0%; multivariate HR: 1.21; 95% CI: 1.03 to 1.42) compared with those without sCVD. Although the Organ Procurement and Transplant Network (OPTN) database is one of the largest and most detailed databases for patients with advanced heart failure, the authors note the limitation of the OPTN database to identify the type and clinical severity of sCVD. The authors conclude that sCVD must be taken in context with other comorbidities and should remain a relative contraindication to transplantation listing, which is well supported by their thoughtful analysis.
A history of cerebrovascular disease among heart failure patients is common, but has not consistently been identified as an independent risk factor for death. Lee et al. (3) identified prevalent cerebrovascular disease among 17% to 22% of patients hospitalized with heart failure (HF), whereas 7% to 12% of the ambulatory patients in the CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) studies had cardiovascular disease (CVD) (4). In the EFFECT (Enhanced Feedback for Effective Cardiac Treatment study) multivariate mortality model, CVD increased the relative risk of death by 1.43-fold at 30 days (p = 0.01) and by 1.36-fold at 1 year (p = 0.03), whereas a history of stroke was not statistically significant in the CHARM program's multivariate survival model or in follow-up of patients receiving implantable cardioverter-defibrillators in Canada (3–5). The inconsistent link between sCVD and HF death results from the high proportion of patients with HF who die of pump failure and sudden cardiac death (62% in the SCD-HeFT [Sudden Cardiac Death-Heart Failure Trial]) and the smaller proportion (18% in the SCD-HeFT) who die of noncardiac vascular events, such as stroke (6). HF is also associated with a higher incidence of stroke compared with the general population (HR: 2.9 vs. general population, 0.8% to 3.2% over 5 years), and older data suggest an inverse relationship between ejection fraction and thromboembolic stroke (HR: 1.18 for each 5% decrease in ejection fraction, p = 0.03) (7,8).
sCVD, diabetes, ischemic etiology, and ventricular assist device (VAD) support were found to be important predictors of stroke among post-transplantation patients in the current study. The authors demonstrate that the greatest single risk factor for post-transplantation stroke is previous sCVD. However, other risk factors in combination or alone may quickly approximate the risk of sCVD as a single factor. Using estimates from the current study, a registrant with a VAD and diabetes mellitus type 2 (estimated HR for stroke: 2.3) would have almost the same relative risk of post-transplantation stroke as registrant with sCVD (HR: 2.41; 95% CI: 2.0 to 2.9). If we accept that a high stroke risk is sufficient to defer listing for transplantation, then an equitable risk assessment for stroke would necessarily include other factors with a comparable risk of post-transplantation stroke.
Compared with the hospitalized patients in the EFFECT registry, in which the prevalence of CVD was 17% to 22%, the authors report a much lower prevalence of pre-transplantation sCVD of 6% (3). The rate of stroke was 4% in those with sCVD and 1.4% in those without sCVD, suggesting a lower incidence of stroke post-transplantation than before transplantation. The absolute difference in prolonged and poor functional status between those with known sCVD and those without sCVD is only 0.7% or 1.21 times the risk of dysfunction in the non-sCVD group. We can infer from these data that a significant amount of patient selection occurs before transplantation listing that limits the impact of sCVD in the post-transplantation population. This practice is consistent with current guidelines and expert recommendations, which emphasize the need to consider the severity of symptoms when cerebrovascular disease is present (9). When considering the high risk of death among transplantation registrants, of whom 90% underwent transplantation from status 1A or 1B in 2008, and the absence of an association between post-transplantation death and pre-transplantation sCVD, the small difference in functional status decline associated with sCVD seems acceptable (10).
The authors also report a dramatic reduction in the number of strokes among transplant recipients that occur by era, with a 54% reduction in the most recent era. The risk of stroke among the REMATCH (Randomized Evaluation of MEchanical Assistance for the Treatment of Congestive HEart Failure) study was 5%, which is similar to the post-transplant risk of stroke among those with prior sCVD (11).
The increase in left ventricular assist device (LVAD) use over time may affect post-transplantation stroke rates. More than 50% of all status 1A registrants are on VAD support at transplantation. Stroke was frequently seen with first-generation volume-displacement VADs, and performing a transplantation in those on VAD support produced a 53% higher risk of stroke post-transplantation. The REMATCH stroke rate among patients on LVAD support was 19% per year (11), which has decreased to 13% per year with axial-flow devices (12). The rate of stroke is lower post-transplantation than during VAD support, making transplantation more attractive than LVAD support with regard to stroke outcomes with current LVADs.
Stroke can be a potentially devastating morbidity among both those with HF or those who have received a transplant to ameliorate the profound symptoms associated with end-stage HF. The transplantation process maximizes survival and quality of life for HF patients with the limited resource of available donor hearts. The small difference in long-term disability between those with and without pre-transplantation sCVD suggests adequate stewardship for candidate selection among transplantation programs. In the current era, the rates of stroke post-transplantation are lower than rates among those with severe HF and LVAD support. The current analysis is a novel assessment of stroke risk among transplant recipients and supports recommendations of treating a history of cerebrovascular disease as a relative contraindication to cardiac transplantation.
Dr. Levy has received financial support from HeartWare and Thoratec. Dr. Dardas has reported that he has no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the view of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Patlolla V.,
- Mogulla V.,
- DeNofrio D.,
- Konstam M.A.,
- Krishnamani R.
- Pocock S.J.,
- Wang D.,
- Pfeffer M.A.,
- et al.
- Lee D.S.,
- Tu J.V.,
- Austin P.C.,
- et al.
- Packer D.L.,
- Prutkin J.M.,
- Hellkamp A.S.,
- et al.
- Mancini D.,
- Lietz K.
- ↵OPTN/SRTR Annual Report Table 11.4: Transplant Recipient Characteristics, 1999 to 2008. http://optn.transplant.hrsa.gov/ar2009/1104_can-last-stat_hr.htm. Accessed April 25, 2011.
- Lazar R.M.,
- Shapiro P.A.,
- Jaski B.E.,
- et al.