Heart failure (HF) is a staggering clinical and public health concern associated with significant morbidity, mortality, and healthcare expenditures. Despite multiple advances in optimal medical therapy, many patients inevitably still advance toward end-stage disease.1,2
Cardiac assist devices are perhaps the greatest paradigm shift in the history of HF treatment.3 The use of left ventricular assist devices (LVADs) in patients with advanced HF has been proven to be superior to medical therapy and has resulted in a meaningful survival benefit.4 Nevertheless, the use of LVADs has not been without the risk of adverse effects.5 Among well-described complications are bleeding, pump thrombosis, neurological events, right ventricular HF, and infections.5–8
Since the introduction of LVADs in the realm of HF therapy, sex-based disparities with higher risk for women have been reported. Nonetheless, sex-specific data on mechanical circulatory support are somewhat limited. Initially, women were woefully underrepresented in the clinical trials of pulsatile-flow VADs, largely owing to the fact that the older-generation devices were larger and less accommodating in women with smaller body size.4,9 Since the introduction of continuous-flow LVADs (CF-LVADs), multiple studies have attempted to explore sex-related differences in morbidity and mortality in patients undergoing implantation of these newer devices. However, overall conclusions are unclear as the results of these studies have been somewhat contradictory and brimming with important limitations.
The aim of this study is to further assess sex-related disparities in the development of common complications associated with the implantation of a CF-LVAD, through a comprehensive systematic review and meta-analysis of published studies.
We systematically searched Medline, Embase, Scopus, and the Cochrane Library from January 2008 to January 2017. No language limits were used. Databases were searched with the following alternatives: “left-ventricular assist device,” “LVAD,” “continuous-flow left ventricular device,” “CF-LVAD,” and “ventricular assist device,” “VAD.” These terms were searched individually with “gender” OR “sex,” combined by the Boolean term “AND.” This strategy was used both as Medical Subject Headings (MeSH) terms if available and as free text. Reference lists from all included studies were manually searched for additional studies.
To be eligible, studies required to meet the following inclusion criteria: 1) describe complications associated to the implantation of CF-LVADs; 2) outcomes had to be specifically reported with sex distinction; and 3) age of the patients included had to be greater than 18 years. We excluded studies containing other types of ventricular assist devices (pulsatile-flow device, isolated right ventricular assist device [RVAD], biventricular assist device, or total artificial heart) and if the outcomes were not evidently distinguished according to sex. Three investigators independently reviewed the study titles, abstracts, and full-length articles to determine study inclusion and exclusion. These reviewers also independently abstracted the study design, patient baseline characteristics, and relevant outcomes. An electronic datum form was utilized to compile abstracted information. Differences were adjudicated by consensus and by the senior author, when needed.
Quality of Studies in the Analysis
The quality and bias of cohort studies was assessed using the Newcastle–Ottawa Scale.10 In this scale, each study receives a total of 0–9 points according to the methodological quality of participant selection, comparability of groups, and outcome assessment. Publication bias was assessed with funnel-plot analysis and evaluation for symmetrical distribution of trials with similar weights.
The study was performed according to recommendations of the Cochrane Collaborations and in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.11 Meta-analysis was performed using a random-effects model to determine risk associated with CF-LVADs and all-cause mortality. In secondary analysis, specific complications associated to CF-LVAD implantation were studied in a similar manner. Outcomes analyzed included incidence of stroke, right HF necessitating RVAD implantation, occurrence of acute renal failure after LVAD implantation, infection specifically related to the driveline or the device, and bleeding defined as a major bleed that required re-exploration. With the complications that resulted statistically relevant, we then performed a sub-analysis with only those studies that specified inclusion of a single device (axial [HeartMate II] or centrifugal-flow device [HeartWare]). Among studies, heterogeneity of risk estimates was examined using a standard χ2 test and I2 statistic for heterogeneity. Results are presented as odds ratios (OR) with 95% confidence intervals (CIs) and p values. A p value of <0.05 was considered statistically significant. The results from included studies were combined for each outcome to give an overall estimate. Continuous variables were compared using the t-test. Categorical data were compared using the χ2 test, unless the frequencies were small, in which case a Fisher exact test was used. For the statistical analyses, we used Review Manager 5.1 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and GraphPad (GraphPad Software, San Diego, CA, USA).
Study Search and General Characteristics
The search retrieved 943 citations. Of these, 210 were duplicates and 679 were not related to the study question based on title and abstract review. Fifty-four studies were fully screened and assessed for potential inclusion. Of these 54 studies, 10 fulfilled all criteria for inclusion (Figure 1). Details of the included studies and baseline characteristics of the patients therein are listed in Table 1. Overall, 4,493 patients were systematically reviewed and included for analysis. The patients were mostly men (76.5%). The body surface area of the women included was smaller (1.8 ± 0.24 in women vs. 2.09 ± 0.25 in men). Women were more likely to have nonischemic cardiomyopathy (NICM) than ischemic cardiomyopathy (ICM) as the cause of HF (NICM: 71.55% in women, 51.6% in men; ICM: 28.45% in women, 48.33% in men). The type of CF-LVAD implanted was fairly similar in both sexes (axial: 72.8% in women, 81% in men; centrifugal: 27% in women, 19% in men). The rest of the baseline characteristics described in the included studies (age, INTERMACS profile, inotrope requirement before LVAD implantation, left ventricular ejection fraction, bridge to transplant [BTT] versus destination therapy [DT]) appear to be similar in both sexes. Most of the included studies performed multivariate analysis for preoperative factors or baseline characteristics.
The nonrandomized published manuscripts included in the analysis were considered medium- to high-quality studies by the Newcastle–Ottawa Scale, with scores ranging from 5 to 9 points10 (see Table S1, Supplemental Digital Content, https://links.lww.com/ASAIO/A204). On funnel-plot analysis, studies occupied a symmetrical distribution according to weight and converged toward the pooled effect as the weight increased (Figure 2). Therefore, there is no evidence of publication bias.
The rate of overall stroke was higher in women (OR 1.94; 95% CI 1.32–2.84; p = 0.0007). This was true for ischemic strokes (OR 2.03; 95% CI 1.21–3.42; p = 0.008), as well as for hemorrhagic strokes (OR 2.03; 95% CI 1.21–3.42; p = 0.008) (Figure 3). Women were also more likely to develop right HF necessitating RVAD implantation (OR 2.12; 95% CI 1.08–4.15; p = 0.03). There was no significant difference in renal failure (OR 1.22; 95% CI 0.87–1.71; p = 0.26), driveline or device-related infections (OR 0.91; 95% CI 0.66–1.26; p = 56), or bleeding requiring re-exploration (OR 1.2; 95% CI 0.81–1.78; p = 0.35) (Figure 4). Furthermore, overall mortality on CF-LVAD was similar in both groups (OR 1.05; 95% CI 0.81–1.36; p = 0.71) (Figure 5). When analyzing stroke by type of device, the overall stroke was also higher in women receiving axial-flow devices (OR 2.96; 95% CI 1.96–4.45; p ≤ 0.00001) when compared with men. There were not enough studies evaluating neurological outcomes in solely centrifugal-flow devices; thus, this analysis did not reach statistical significance (Figure 6). For the rest of the outcomes, there were insufficient data to determine statistically significant device-specific outcomes.
There are well-described sex-related differences in a great variety of cardiovascular diseases including coronary and valvular heart disease, arrhythmias, and HF.22,23 Little attention has been given to sex variances in HF and HF-related procedures, despite evidence that there are clear differences between men and women in etiology and in disease prognosis.23,24 Sex-based disparities with higher risk for women have been well reported after CF-LVAD implantation.12–21 In previous reports, female sex has been found to be an important risk factor for the development of stroke.14–18 Although not uniformly described, women also appeared to be more likely to develop early right HF requiring right ventricular support,13,21 renal and respiratory dysfunction,13 and postoperative bleeding,15 and require longer duration of inotropic support.21 Although there is a trend toward more unfavorable outcomes in women, the influence of gender in well-known complications after LVAD is still somewhat contradictory among published data. Our pooled analysis confirms that female sex is a risk factor for cerebrovascular events and right HF necessitating RVAD after CF-LVAD implantation. However, other adverse outcomes explored such as renal failure, driveline or device-related infections, and bleeding requiring re-exploration appear to be similar in men and women.
The cause for sex-related differences after CF-LVAD implantation remains unknown. There are speculations as to why these disparities exist, yet concrete data are lacking. Among the difficulties that arise when attempting to analyze sex-related complications after LVAD implantation, is the lack of description of sex-related outcomes in the trials that have been set forward to evaluate LVAD efficacy and safety. Moreover, women have been greatly underrepresented in all of the LVAD trials to-date. In the REMATCH study,4 considered the initial landmark trial that established the benefit of LVAD, only 22% of the LVAD population included were women. Subsequently, the ROADMAP study25 included 23% women in their LVAD arm and, lastly, the most recent MOMENTUM 326 included only 20.4% women. In these trials, LVAD therapy proved overall benefit in functional capacity and quality of life, but against a real risk of adverse events while on LVAD support. These adverse events were not stratified according to sex; thus, the results are unhelpful when trying to reach sex-based conclusions.
Some authors have suggested that women are often referred for LVAD implantation later, when their HF is more advanced. This could potentially explain the noted increased risk in RVAD requirement experienced by women. In this regard, an analysis of pulsatile LVADs implanted at Columbia between 1990 and 2002 showed that women presented with more advanced HF than men did, and multivariate analyses revealed that greater severity of illness, not sex, accounted for these differences.27 Most baseline characteristics that would allow assessment of disease severity and possible associated comorbidities are poorly and not uniformly reported in the included studies.
Stroke, both ischemic and hemorrhagic, appears to be one of the most serious complications after LVAD therapy. Recent evidence has shown that the risk of stroke among patients with LVAD is bimodal, with highest risk at time of implant and increasing risk again after 9–12 months.28 Unfortunately, the studies included did not clearly define whether the neurologic events occurred during the initial hospitalization or after discharge. The only study that very clearly defines the timing of strokes is Bashir et al.12 In their study, 6 strokes occurred within the first 30 days of LVAD placement, and 13 occurred after 30 days. Determining the timing of strokes might allow management of modifiable pre- or postoperative risk factors that lead toward a higher incidence of neurological events.
Some authors have indicated that patients with centrifugal pumps are more likely to develop cerebrovascular accidents than those with axial-flow pumps.29–31 There are currently no data evaluating device-specific complications distinguished by gender. With the intent of discerning whether the higher stroke rate in women might be confounded by the type of device they received, we performed a sub-analysis with only those studies that included a single device. To this matter, it appeared that women were still more likely to have a higher burden of strokes when receiving axial-flow devices. The analysis in centrifugal-flow devices was not statistically significant; notwithstanding, the fact that female sex remained a risk factor for stroke in axial-flow LVADs is suggestive that the type of device implanted does not play a significant role in the overall higher incidence of stroke in women.
Overall, it is well known that recipients of CF-LVADs have significant alterations in coagulation proteins, platelets and von Willebrand factor, resulting in an increased thrombotic profile when compared with the general population.15,32–34 Detailed information regarding the coagulation profile of these patients, as well as von Willebrand factor and anticoagulation therapy at time of neurologic event, would have provided valuable information for an interesting analysis, but they are rarely and inconsistently reported in the studies included in this review. Efforts have been set forward in the attempt of identifying the basis of the higher thrombotic risk experienced by women. A recent statement from the American Heart Association/American Stroke Association recognized that women differ from men in a great variety of ways, including genetic differences in immunity, hormonal influences, response to anticoagulation, and in the higher incidence of some well-known risk factors for stroke, such as obesity/metabolic syndrome, atrial fibrillation, and migraine with aura.35 Hormonal influences, such as the use of oral contraceptives or hormone replacement therapy, have also been associated with an increased risk of venous thromboembolism.36,37 In addition, the Framingham Heart Study demonstrated that the risk of ischemic stroke in women varies with the age of natural menopause.38 Furthermore, some authors have hypothesized that variances in the pharmacokinetics and pharmacodynamics of anticoagulation and antiplatelet drugs also account for the higher risk of thromboembolism in women.39 All of these underlying risk factors may play a role in the higher rates of stroke in women after CF-LVAD use, but, regrettably, details of these variables were unavailable in the studies included in our analysis. Further research is necessary to determine whether the differences in neurologic events observed after LVAD implantation are due to sex-related responses to the nuances of medical therapy or due to sex differences inherent to the higher thrombotic profile that can potentially be acquired by some women.
In spite of the higher risk that women have in some complications after LVAD implantation, our study is in agreement with prior findings that show that overall survival is not significantly different. This can suggest that the disease process is particularly different in women and should not be approached in the same manner as in men. Regrettably, although women comprise more than half of all patients diagnosed with HF, they continue to be underrepresented in most clinical trials, including those for the study of LVADs.
It is worth noting, that the studies describing sex-related discrepancies in outcomes after LVAD implantation have had multiple limitations, posing important restrictions in our analysis. Most of the limitations are inherent to the study design and retrospective nature of the included studies. Perhaps the most important limitation has been the lack of substantial baseline characteristics, not considering pertinent patient information before LVAD implantation. Similarly, most studies excluded important variables in the follow-up period. Without a consonant report of pre-LVAD and post-LVAD variables, reaching conclusions as to why these differences exist remains challenging. Adequate prospective studies are needed to include these important variables that can serve as confounding factors and guide a better understanding of the mechanisms underlying sex-specific outcome disparities.
To our knowledge, this is the first meta-analysis and systematic review evaluating sex-related differences in outcomes after CF-LVAD implantation. Our pooled analysis suggests that women are at a significantly greater risk of experiencing cerebrovascular events and right HF necessitating RVAD after CF-LVAD implantation when compared with men, without necessarily affecting overall mortality. Although recent advancements in LVAD technology have enhanced survival and quality of life among LVAD recipients, multiple challenges remain. Sex-related disparities are still a considerable problem after LVAD implantation. Despite these known sex-based differences, guideline recommendations for HF are the same for women and men, mainly due to the lack of adequate clinical trials describing sex-specific outcomes. Our analysis should serve as an enlightening source of motivation to set forward more studies that analyze the possible underlying mechanisms that explain these differences. Understanding sex-based disparities after LVAD implantation is crucial in order to tailor individual therapeutic strategies for these subgroups.
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