Management of the heterogeneous disorder of heart failure (HF) is particularly complex in the presence of comorbidities [1‐3]. Nearly 60% of adults with HF have five or more chronic comorbidities, a percentage that has increased dramatically over the last twenty years [4]. Both cardiovascular and non-cardiovascular comorbidities observed among adults with HF contribute to condition development, progression and prognosis [5‐7]. Comorbidities in HF also vary in etiological association [8], with some conditions like myocardial infarction and peripheral vascular disease having risk factors in common, and others such as cerebrovascular disease and dementia having a direct causal link. Thus, although the influence of specific and/or the number of comorbidities are important to our understanding of HF complexity, identifying naturally occurring patterns among comorbidities may be more helpful in identifying subgroups of HF patients who are more vulnerable to poor outcomes and who would benefit from tailored management strategies [9, 10].

Accordingly, the primary aim of this study was to identify and characterize distinct, common, and naturally-occurring profiles among chronic comorbidities in adult hospitalizations for HF. To quantify the clinical relevance of these findings, we also sought to quantify associations among observed comorbidity profiles and the inpatient outcomes of all-cause death, length-of-stay (LOS) and costs.

Data from the 2009 Agency for Healthcare Research and Quality (AHRQ) Health Care Utilization Project Nationwide Inpatient Sample (NIS) were used for this study. The NIS is the largest publicly available all-payer inpatient care database in the U.S. The 2009 NIS contains all discharge data from a sampling frame of 4,390 hospitals located in 44 States, representing an approximate 20% stratified sample of U.S. community hospitals. This study was determined to be exempt from ethical review by the Oregon Health & Science University institutional review board because all NIS data are de-identified and includes several other safeguards to protect the privacy of individual patients, physicians and hospitals. This study conforms to the principles of the Declaration of Helsinki. All hospital discharges were examined for the diagnosis of HF by identifying AHRQ clinical classification software [11] diagnosis category 108 (i.e. congestive HF, nonhypertensive (International Classification of Diseases, 9^th Edition, Clinical Modifications (ICD-9-CM) codes 398.91, 428.0 428.1 428.20 428.21 428.22 428.23 428.30 428.31 428.32 428.33 428.40 428.41 428.42 428.43 428.9)) [12] and additional ICD-9-CM codes indicative of HF (402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93) [13, 14] as the principal diagnoses. In the NIS, the principal diagnosis was the condition established after study to be chiefly responsible for prompting the hospitalization. Hospitalizations for HF were also verified as being urgent or emergent (i.e. non-elective).

Management of HF is complicated by prevalent cardiovascular and non-cardiovascular comorbidities [25]. In this nationally-representative inpatient sample of 192,327 adult hospitalizations with a principal diagnosis of HF, there was an average of 7.5 comorbidities and the vast majority of hospitalizations (82.4%) were categorized as having a high Charlson comorbid burden. The main finding of this study is the identification of four distinct and naturally occurring comorbidity profiles that were associated with significant differences in the all-cause inpatient outcomes of death, length-of-stay and cost. Relative to the 46.7% of hospitalizations with a "common" comorbidity profile, the 19.6% of HF hospitalizations fitting a "lifestyle" profile had longer length-of-stay and greater costs, and the 29.6% of HF hospitalizations within a "renal" comorbidity profile and the 4.1% of HF hospitalizations with a "neurovascular" comorbidity profile were associated with higher risk of inpatient death, longer length-of-stay and greater costs.

Similar to the findings of other studies, we observed a direct relationship between the number of comorbidities [26‐28] as well as categories of Charlson comorbid burden [29] and clinical outcomes among adults with HF. Specifically, we observed an adjusted 3%-5% increase in the risk of death, extension in length-of-stay and accrual of inpatient costs for additional comorbidities. The number of comorbidities and the proportion of discharges associated with 5 or more comorbidities in this sample are greater than prior reports in HF [4, 28], which can be explained, at least in part, by our inclusion of 32 comorbidities that were of both cardiovascular and non-cardiovascular origin. An extreme minority of hospitalizations in this sample involved patients with a low comorbid burden; thus, we compared hospitalizations fitting a moderate and high Charlson comorbid risk. High Charlson comorbid burden was associated with 12%-16% increase in the risk of death, extension in length-of-stay and accrual of inpatient costs compared with hospitalizations for adults with a moderate comorbid burden. In sum, our findings provide further evidence in support of both the number of comorbidities and categorization of comorbid burden as having a significant influence on inpatient outcomes in HF.

There is elegance in the simplicity of counting comorbidities, considering thresholds that represent complex comorbidity (i.e. 5 or more), and weighing counts of comorbidities based on established associations with 1-year mortality (i.e. Charlson). A major limitation to these approaches to comorbidities in HF, however, is the inability to consider how some comorbidities are naturally independent, others have common risk factors and/or pathogenic pathways, and others still have direct causation [8]. Moreover, single comorbidity inventories often omit key conditions that are highly-prevalent in HF (e.g. the Charlson excludes hypertension, and the AHRQ comorbidities do not include myocardial infarction), and ineffectively capture condition severity (e.g. the Charlson does not differentiate diabetes with and without complications, and the AHRQ comorbidities do not differentiate mild from moderate to severe liver disease). Thus, our finding of four distinct, naturally-occurring profiles among comorbidities in adult HF hospitalizations builds upon prior research that has involved single comorbidity inventories or considered all comorbidities as being etiologically and statistically independent.

The largest comorbidity profile we observed involved the fewest and common comorbidities. In fact, the only differentiating factors to identity patients fitting this profile were prevalent HF comorbidities (e.g. hypertension, chronic pulmonary disease, and uncomplicated diabetes) and the absence of renal disease, which had an overall prevalence of 39% but only affected 0.5% of discharges in this profile. Based on this sample, there is an estimated 455,851 hospitalizations in the U.S. for HF patients fitting this comorbidity profile annually, and they experience the most favorable inpatient outcomes. The next hazardous profile we observed was differentiated by comorbidities that are linked to lifestyle, including 100% prevalence of uncomplicated diabetes, 84% prevalence of hypertension, 40% prevalence of chronic pulmonary disease, and 27% prevalence of obesity. The triad of diabetes, hypertension and obesity is well-recognized as integral characteristics of metabolic syndrome [30], and majority of chronic pulmonary disease is thought to be attributable to cigarette smoking [31]. There is an estimated 191,595 annual hospitalizations for HF patients fitting this lifestyle comorbidity profile that is associated with longer length-of-stay and greater inpatient cost. Fitting the lifestyle profile on discharges for HF should serve as a red flag for greater healthcare utilization, and interventions to reduce the risk of poor inpatient outcomes for this profile should be tailored to improving lifestyle in general in addition to treating specific comorbidities. Since hypertension and diabetes mellitus were prominent features of both the common and lifestyle comorbidity profiles, dietary modifications and aerobic exercise are two specific lifestyle recommendations that may be helpful in the reduction of cardiovascular risk in these two groups [32]. It is also known that hypertension and obesity are more prevalent among HF patients with preserved versus reduced ejection fraction [33]; thus, interventions to reduce the risk of poor clinical outcomes may be further tailored by HF type within the observed comorbidity profiles.

The next hazardous profile we observed was centered on a high prevalence of renal disease (82%) and diabetes with complications (31%). The combination of renal disease and diabetes has been shown by others to be associated greater risk of death and hospitalization in HF [34]. Over 3/4 of HF discharges within this renal profile also had hypertension and slightly more than 1/3 had fluid and electrolyte disorders. Diabetes and hypertension are widely recognized as the leading causes of renal disease [35], and cardiorenal syndrome [36] is a challenging condition to manage particularly during acute hospitalization for HF [37]. Given the nature of these data, it is not possible to understand the temporal and/or causal nature of relationships among the key differentiating comorbidities in the renal or other profiles. But, HF hospitalizations for patients fitting this profile were associated with a 30% increase in the risk of inpatient death and 27% and 24% increases in length-of-stay and inpatient costs, respectively and there is an estimated 289,613 annual HF discharges in the U.S. for patients fitting this comorbidity profile.

The most hazardous comorbidity profile identified was differentiated from the others by extremely high rates of cerebrovascular disease, and the highest prevalence of paralysis, myocardial infarction, peripheral vascular disorders, neurologic disorders and depression. Peripheral vascular disease is often paired with comorbid cerebrovascular disease [38], and is a determinant of worse outcomes in patients with myocardial infarction [39]. There also is a link between both cerebrovascular disease [40] and myocardial infarction [41] and depression. Thus, end-organ damage of global vascular disease appeared to be central to this profile. Based on this sample there are more than 39,000 HF hospitalizations for patients fitting this neurovascular comorbidity profile in the U.S. annually; there was a 45% increase in the risk of inpatient death, 34% increase in length-of-stay and 37% increase in inpatient cost associated with discharges for HF patients fitting this profile. Patients fitting the renal or neurovascular profiles upon admission for HF should be assumed to require greater healthcare utilization and should be enrolled in disease management and care transition programs to mitigate the overall impact on global healthcare resources and improve patients’ quality-of-life.

There are several existing schemes for classifying the risk of poor inpatient outcomes in HF. For example, Fonarow and colleagues determined that blood urea nitrogen, admission systolic blood pressure, and serum creatinine were predictive of inpatient mortality among adults admitted for decompensated HF [42]. Coronary artery disease, renal insufficiency and diabetes were more prevalent in the high- versus the low-risk groups in that study. As an additional example, Peterson and group determined that age, systolic blood pressure, blood urea nitrogen, heart rate, serum sodium, coexisting chronic obstructive pulmonary disease, and race were predictive of inpatient mortality among adults admitted for decompensated HF [43]. Thus, the incorporation of coexisting comorbidities into inpatient prognostic models is not new. But, what our findings add to extant knowledge about the influence of comorbidities on inpatient outcomes is a new approach the naturally-occurring clusters of prevalent and coexisting that complicate HF admissions and are associated with significant differences in inpatient outcomes.

Among a large sample of adult hospitalizations for HF, we observed four distinct comorbidity profiles that were associated with large and significant differences in the risk of inpatient death, length-of-stay and inpatient cost. Naturally-occurring patterns of cardiovascular and non-cardiovascular comorbidities, not simply the number of comorbidities, should be the focus of future research and the target of future interventions aimed at reducing the risk of inpatient death and healthcare utilization.