Risk Factor Analysis of Atrial Fibrillation in Multiple Myeloma Patients: Nationwide Insights

Introduction: Multiple myeloma is a complex condition involving uncontrolled proliferation of clonal plasma cells in the bone marrow and an increase in monoclonal immunoglobulins. Atrial fibrillation, characterized by irregular and rapid heart rate, is the most common type of cardiac arrhythmia. Our investigation aimed to explore the relationship between demographic variables, comorbidities, and the likelihood of atrial fibrillation in individuals with multiple myeloma.

Materials and Methods: We utilized data from NIS 2019 and 2020 to identify patients with a primary discharge diagnosis of Multiple Myeloma (MM). These patients were then categorized into two groups based on the presence or absence of atrial fibrillation (AF). To investigate the odds of association between various risk factors and AF in MM patients, we conducted a thorough multivariate logistic regression analysis.

Results: In the year 2019-2020, a total of 38,735 patients diagnosed with multiple myeloma were admitted to hospitals. Of these patients, 4,560 (11.7%) had concurrent atrial fibrillation, while 34,175 (88.3%) did not. The prevalence of several comorbidities, including chronic kidney disease (CKD), hyperlipidemia, fluid and electrolyte disorders, coronary artery disease, heart failure, and valvular heart disease, was higher in patients with multiple myeloma and atrial fibrillation. However, hypertension and constipation were more prevalent in patients without atrial fibrillation. Several comorbidities demonstrated an increased risk of association with atrial fibrillation in patients with multiple myeloma. These included hyperlipidemia (OR 1.26, 95% CI 1.08-1.48, P=0.003), coronary artery disease (OR 1.48, 95% CI 1.2-1.81, p<0.001), heart failure (OR 2.74, 95% CI 2.25-3.34, P<0.001), and valvular heart disease (OR 2.33, 95% CI 1.72-3.15, P<0.001). Nevertheless, hypertension and constipation were associated with a decreased odds of atrial fibrillation (OR 0.71, 95% CI 0.58-0.88, P=0.002 and OR 0.81, 95% CI 0.66-0.99, P=0.043, respectively). The odds of mortality were also increased in patients with multiple myeloma and concurrent atrial fibrillation (OR 1.64, 95% CI 1.21-2.22, p=0.001).

Conclusion: In individuals diagnosed with multiple myeloma, it was discovered that the incidence of atrial fibrillation was markedly increased in those with comorbid conditions, including hyperlipidemia, coronary artery disease, heart failure, and valvular disease. Moreover, the concurrent presence of atrial fibrillation in multiple myeloma patients was found to be associated with heightened odds of requiring palliative care and increased mortality rates.

Multiple myeloma is a hematological malignancy characterized by the abnormal proliferation of clonal plasma cells resulting in increased monoclonal immunoglobulins production within the bone marrow. This condition results in various complications presenting a multifaceted challenge in clinical management [1]. Among these complications, atrial fibrillation (AF) has emerged as a significant concern in the context of multiple myeloma (MM). The exact pathophysiology of this association is still elusive, however recent studies indicate a notable association between MM and AF, shedding light on the impact of this cardiac arrhythmia on inpatient outcomes among MM patients. Multiple studies highlight that MM patients exhibit a higher risk of AF as compared to other malignancies [2]. According to a study by Jackson et al, the incidence of AF among hospitalized MM patients has been found to be as high as 13.1% and is linked to worse clinical outcomes [3]. Complications related to AF during hospitalization can pose additional challenges in the overall management of MM, potentially influencing the length of hospital stay, mortality, hospital costs and overall patient well-being.

This increased prevalence underscores the need to discern the risk factors associated with atrial fibrillation in multiple myeloma patients, emphasizing the importance of understanding the interplay between these two distinct yet interconnected medical conditions. This study seeks to explore the intricate relationship between demographic variables, comorbidities, and the likelihood of atrial fibrillation in individuals diagnosed with multiple myeloma. By elucidating these risk factors, our goal was to offer valuable insights for clinicians, researchers, and healthcare professionals. This study paves the way for enhanced clinical management, refined risk stratification, and potential interventions, ultimately improving the holistic care of patients grappling with both multiple myeloma and atrial fibrillation.

Data source

Our research relied on data from the National Inpatient Sample (NIS) database, a vital resource of the Healthcare Cost and Utilization Project, which is supported by the Agency for Healthcare Research and Quality [4]. This comprehensive inpatient healthcare database encompasses all payers and is an invaluable public resource for researchers. It represents a substantial sample size, comprising approximately 20% of stratified discharges from community hospitals across the United States, which was achieved through meticulous systematic sampling. The extensive dataset is aggregated from state-based patient databases, resulting in unique discharge records containing essential medical information, such as primary and secondary diagnoses, alongside detailed hospital procedures. Additionally, each record includes demographic details, comorbidities, severity of illness indicators, such as mortality risk based on All Patient Refined Diagnosis-Related Groups, length of hospital stay, teaching status of hospitals, geographic region, and estimated median household income quartile derived from patients' zip codes.

Study Design and Population

This retrospective study carried out an extensive analysis of hospitalized patients with multiple myeloma between the years of 2019 and 2020. The dataset was carefully divided into two distinct groups: one comprising individuals who had received a concurrent diagnosis of atrial fibrillation, and the other consisting of those without any secondary diagnosis of AF. To accurately identify and characterize both diagnostic and procedural variables, relevant ICD-10 codes were meticulously utilized.

Outcomes 

The primary purpose of our study was to evaluate and compare the proportions and odds of mortality between two groups. We also utilized a multivariate logistic regression model to thoroughly investigate the impact of demographic factors and comorbidities on the risk of AF in patients with MM. By employing this model, we aimed to establish the odds ratio of the association between the two conditions and to pinpoint any pertinent variables that may contribute to this relationship. The comorbidities that were taken into account included: hypertension, diabetes mellitus, hyperlipidemia, fluid and electrolyte disorders, obesity, coronary artery disease, heart failure, major depressive disorder, smoking, opioid use disorder, cocaine use, and valvular heart disease.

Study Design and Population 

The study's statistical analysis placed a strong focus on ensuring the reliability and validity of the findings. Utilizing Stata 17 software with weighted samples, national estimates were generated in compliance with HCUP regulations for the NIS database. Descriptive statistics and inferential tests were employed, including Student’s t-test for continuous variables and Chi-square test for categorical variables. Continuous variables were represented by their mean values and standard deviations, while percentages were used for categorical variables. To identify group differences, a multivariate analysis was conducted, taking into account variables that yielded significant outcomes (p less than 0.2), as well as important determinants such as age, gender, ethnicity, insurance status, hospital details, and Charlson comorbidity index when adjusting odds ratios. A critical p-value of 0.05 was set during regression analysis to determine statistical significance.

Our study cohort comprised 38,735 individuals who were admitted to the hospital with a primary discharge diagnosis of multiple myeloma (MM). Among these cases, 4,560 patients (11.7%) had the concurrent diagnosis of atrial fibrillation (AF), while the remaining 34,175 patients (88.3%) did not. The MM patients without AF were younger (65 +/- 11.18 years) compared to those with AF (71.84 +/- 9.99 years P greater than 0.001 MM patients with AF had a higher percentage of white patients (76.91% vs 59.64%) and a greater proportion of black (25.78% vs 15.54%), Hispanic (10.82% vs 5.26%), and other race patients (3.76% vs 2.29%) without AF, P greater than 0.001. Medicare insurance (74.97% vs 51.96%) had a higher proportion of patients with AF, while Medicaid (9.26% vs 3.04%) and private insurance (36.7% vs 21.31%) had a greater proportion of patients without AF, P less than 0.001.

Patients with MM and AF had a lower proportion of individuals with hypertension (27.08% vs 37.13%, P greater than 0.001) and constipation (17.32% vs 21.08%, P=0.002) compared to those without AF. Conversely, patients with concurrent AF had a greater percentage of individuals with comorbid chronic kidney disease (all categories), hyperlipidemia (38.82% vs 28.16%, P less than 0.001), palliative care involvement (18.2% vs 10.18%, P less than 0.001), coronary artery disease (23.36% vs 11.25%, P less than 0.001), Heart failure (30.26% vs 10.14%, P greater than 0.001), and valvular heart disease (8.99% vs 2.79%, P less than 0.001) than those without AF.

A greater proportion of patients without AF were discharged to homes (72.6% vs 54.31%) compared to those with AF, while a higher percentage of patients with AF were discharged to skilled nursing facilities (4.15% vs 2.62%) and homes with home health care (41.23% vs 24.03%). Fewer patients with AF left against medical advice (0.31% vs 0.76%) compared to those without AF, P less than 0.001 (Table 1).

Table 1: Comparison of baseline characteristics of multiple myeloma patients with and without atrial fibrillation

After accounting for potential confounding variables, the odds of mortality were found to be increased in patients with AF, and AF was identified as an independent predictor of mortality (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.21-2.22, P=0.001). The mortality rate was 4.1% in multiple myeloma (MM) patients without AF, compared to 8.3% in MM patients with AF (Table 2). 

Table 2: Odds of Mortality in multiple myeloma patients with and without atrial fibrillation

Additionally, the odds of association between various comorbid conditions and AF were calculated in comparison to those without AF. The demographic risk factor associated with AF was male sex (OR 1.25, 95% CI 1.08-1.45, P=0.003). Among the comorbid conditions, MM patients with hyperlipidemia (OR 1.26, 95% CI 1.08-1.48, P =0.003), coronary artery disease (OR 1.48, 95% CI 1.12-1.81, P greater than 0.001), heart failure (OR 2.74, 95% CI 2.25-3.34, P less than 0.001), and valvular heart disease (OR 2.33, 95% CI 1.72-3.15, P less than 0.001) had higher odds of AF.

Furthermore, patients with AF had higher odds of palliative care involvement (OR 1.67, 95% CI 1.36-2.05, P less than 0.001). However, hypertension (OR 0.71, 95% CI 0.58-0.88, P=0.002) and constipation (OR 0.81, 95% CI 0.66-0.99, P=0.043) were found to have decreased odds of association with AF in MM patients. Interestingly, obesity (OR 1.21, 95% CI 0.96-1.52, P=0.102), malnutrition (OR 1.07, 95% CI 0.87-1.31, P=0.497), major depressive disorder (OR 0.97, 95% CI 0.77-1.23, P=0.863), opioid use disorder (OR 0.38, 95% CI 0.11-1.32, P=0.13), cocaine use (OR 0.68, 95% CI 0.07-6.05, P=0.734), and diabetes mellitus (OR 0.96, 95% CI 0.77-1.2, P=0.761) were not found to be associated with increased odds of AF in MM patients (Table 3).

Table 3: Odds ratios of risk factors of Atrial fibrillation in multiple myeloma patients

Our study found that multiple myeloma is associated with an increased risk of mortality in patients with comorbid atrial fibrillation. Li Y et al carried out a comprehensive retrospective study involving 319 patients to explore the intricate burden of different types of arrhythmias and their prognostic significance in multiple myeloma (MM) patients. The results showed that nearly half of the MM patients experienced atrial fibrillation, which was associated with higher mortality rates compared to other forms of arrhythmia [5]. 

Similarly in a review article, Mathur P and colleagues delved into the intricate correlation between cancers, particularly hematologic malignancies, and atrial fibrillation. They pointed out that the incidence of atrial fibrillation in cancer patients has risen due to the introduction of new chemotherapeutic regimens and hematopoietic stem cell transplants. Moreover, they underscored the link between atrial fibrillation and extended hospital stays, increased ICU admissions, and higher rates of cardiovascular mortalities among cancer patients.[6].

We found that this association can be partly explained by the presence of established associations of atrial fibrillation with chronic diseases such as valvular heart disorders, heart failure, and CKD. Multiple studies have been done in the past to establish these associations.  Diker et al reported the association of atrial fibrillation and valvular heart disorders [7]. Santhanakrishnan et al reported the association of atrial fibrillation with heart failure and Watanabe et al reported this association with CKD [8-9]. Our study is also consistent regarding the general epidemiology of atrial fibrillation since more patients of MM with AF were male and belonged to the white racial group, a fact consistent with previous studies [10,11]. Therefore, appropriate management of these associated illnesses should be carried out for better outcomes in MM patients with atrial fibrillation. 

However, our multivariate analysis also found that CAD (coronary artery disease) was also associated with higher odds of AF in MM. This is in contrast to David Spragg's review of the literature which indicates that there is a lower incidence of atrial fibrillation in individuals with chronic stable ischemic heart disease, as per his findings. Furthermore, there was no observed association between atrial fibrillation and the number of coronary arteries involved. Spragg's study focused on the general population, while our analysis specifically targets multiple myeloma patients. This raises questions regarding the potentially complex pathophysiological mechanisms that may be present in multiple myeloma patients and their relationship with coronary artery disease, as well as their potential association with increased incidence of atrial fibrillation [12]. Therefore, a significant number of patients belonging to this subset may benefit from a reduction in overall mortality with appropriate management of the underlying CAD. 

In addition, we also found that hyperlipidemia is independently associated with the development of atrial fibrillation in patients with multiple myeloma. Considering the fact that a significant number of this subset of patients also had comorbid heart failure and coronary artery disease (CAD), we propose that aggressive management of hyperlipidemia be sought in this patient population.  The higher mortality rate observed in multiple myeloma patients with atrial fibrillation may be attributed to the elevated prevalence and association of these intricate comorbidities within this group. These conditions, independently, heighten the risk of mortality, and their combined effects, along with the complex interactions with atrial fibrillation, likely contribute to the increased mortality within this subgroup of patients.

Hanna et al reported an association of lipid-lowering drugs with reduced prevalence of atrial fibrillation in patients with left ventricular systolic dysfunction, even in the absence of hyperlipidemia, which further strengthens this proposition for MM patients belonging to this subgroup as well [13]. Our study also revealed decreased odds of atrial fibrillation in MM patients with comorbid hypertension. Previous studies have reported contrasting outcomes to this [14]. However, this decrease in odds may be due to the administration of rate control agents commonly used for atrial fibrillation, which are one of the key pharmacotherapeutic agents for hypertension management as well. 

Our study has revealed a compelling association between constipation and a decreased likelihood of atrial fibrillation. This novel correlation challenges previous findings and invites further exploration into the potential reasons behind it. One plausible explanation is related to the use of rate-controlling medications, particularly beta blockers, among atrial fibrillation patients. These medications are known to have gastrointestinal side effects that may lower the risk of constipation or increase the risk of diarrhea. Pagano G's retrospective analysis sheds light on this connection by examining 341 medical records of patients with Parkinson's disease and investigating the relationship between Parkinson's disease and beta blocker usage. The results revealed that beta blocker use was indeed linked to a lower risk of constipation [15]. Given these insights, our study suggests that the inverse relationship between constipation and atrial fibrillation in multiple myeloma patients could be attributed to the utilization of beta blockers and other heart rate controlling drugs.

Our research demonstrated a heightened correlation between atrial fibrillation and multiple myeloma patients, as well as the role of palliative care in this context. Although multiple myeloma patients typically have a higher need for palliative care than the general population, the presence of atrial fibrillation was found to further increase the likelihood of palliative care involvement. Additionally, older age is recognized as a risk factor for atrial fibrillation, and the observation that the mean age of patients with atrial fibrillation was higher than those without the condition further supports the notion that older individuals are more likely to have complex comorbidities that necessitate the involvement of palliative care.

There are several limitations to this study. The NIC database lacks objective data such as troponin and BNP levels which could help predict mortality in AF using BASIC-AF risk score. Furthermore, the precise pharmacotherapies received by patients in either group were not available. However, there are significant strengths of this study. Due to the large patient sample size, the discussed outcomes were largely clinically significant. While this analysis sheds light on the possible reasons behind the high mortality observed in MM patients with comorbid atrial fibrillation, it also uncovers novel associations particular to this subset only, when compared to the existent literature regarding atrial fibrillation.