We found only a small number (n = 9, or 0.2% of persons) of presumed heart failure cases in a total population of 4018 RA and CD patients. Among these relatively young patients, there was an increase in the relative risk of incident HF that was not statistically significant among patients exposed to TNF-α antagonists compared to patients exposed to other disease modifying agents. Additionally, the clinical details (e.g. interstitial lung disease, valvular abnormalities) of some of the presumed HF cases may have represented an extra-articular feature of the underlying disease process and be unrelated to drug exposure. If patients with these extra-articular disease features were more likely to be treated with TNF-α antagonists, the estimated relative risks would be spuriously increased (confounding by indication). The absolute risk difference of heart failure between the TNF-α antagonist treated RA patients compared to untreated patients was 3.4 cases per 1000 persons, yielding a number needed to harm of 294. Both absolute and relative risk differences for CD patients were negligible.
The risk of heart failure among patients with inflammatory diseases, particularly RA, has been a subject of much discussion in the literature. Recent studies have found that RA patients not exposed to TNF-α
antagonists are at increased risk for both incident HF and excess HF-related mortality compared to non-RA patients [7
]. Only about half of the excess risk of HF in RA patients can be attributed to traditional cardiovascular risk factors [9
], and both rheumatoid factor positivity and extra-articular RA have been shown to be risk factors for cardiovascular mortality [7
]. RA patients may also suffer from disease-related pulmonary and cardiac abnormalities such as interstitial lung disease, secondary pulmonary hypertension and cardiac valvular abnormalities; we observed some of these conditions as described in . If RA patients at greater risk for heart failure due to their underlying disease are more likely to be prescribed TNF-α
antagonists (confounding by indication [11
]), this may account for an observed increased risk of HF in these RA patients. Indeed, studies using only claims data to assess both comorbidities and HF outcomes among RA patients may suffer from a lack of information on important confounders (e.g. body mass index, smoking status, subclinical atherosclerotic vascular disease, valvular disease). In contrast, we are not aware of prior literature suggesting that CD patients are at increased risk for HF (even in the absence of TNF-α
antagonism), although unchecked systemic inflammation might play an aetiologic role [10
]. Additionally, RA and CD patients treated with TNF-α
antagonists could have a higher prevalence of cardiovascular-related comorbidities prior to TNF-α
antagonist initiation, although we did not observe this in our relatively young cohort.
Previous studies among TNF-α
antagonist-exposed persons with auto-immune diseases found no increase in risk of HF. Wolfe and Michaud [3
] found 42 cases of incident HF in a large cohort of RA patients using HF endpoints defined by a combination of patient self-report via questionnaires, physician contact and medical record review. There was no increased risk of incident HF among TNF-α
exposed RA patients compared to those receiving other DMARDs. There were only three cases of incident HF among 2970 patients younger than 50 years (incidence of 1 per 1000), and all were observed in patients receiving only MTX. Concordant with our results, another recent study using administrative claims data showed there was no significant difference in the risk of HF between RA patients exposed to MTX and those exposed to TNF-α
]. There was no specific mention of the risk of HF in younger patients. In that study and in contrast to our case validation process, HF endpoints were determined by using an ICD9-CM code for HF without medical record review.
The strengths of our study include a large cohort of RA and CD patients enrolled in a large U.S. health care organization, approximately half of whom were exposed to TNF-α antagonists during a mean observation period of 18 months. Our results address the safety of TNF-α antagonists in this ‘real world’ setting, which is an important adjunct to results from clinical trials that often are limited to highly selected populations. Incident HF outcomes were sought and rigorously assessed using a sensitive, claims-based strategy followed by abstraction of one in-patient or out-patient medical record that was independently reviewed by two physicians. Using this methodology, we found only nine definite or possible cases of incident HF. It is possible that abstraction of additional medical records for each suspected case of HF might have increased the sensitivity of our approach. However, the 33 suspected cases of HF (0.8% of the entire cohort) preliminarily identified using the claims data could be considered a maximal upper bound of the absolute incidence of heart failure in this population; moreover, after medical record review of the 20 cases that met the Framingham screening criteria, it was clear that there was sufficient information to refute the diagnosis of heart failure for some of them. Another notable strength of our work is that we were able to obtain medical records to identify relevant clinical details of the suspected heart failure cases to identify comorbidities (e.g. morbid obesity, longstanding interstitial lung disease with pulmonary hypertension) that are often under-reported in claims data. Other studies that are limited to claims data alone to determine outcomes may suffer from a lack of information about these and other important and often unmeasured factors that may confound exposure–outcome relationships.
Although the overall absolute incidence of heart failure in this population may be reassuring, the increased but non-significant relative risk of heart failure observed among RA patients may be a source of concern. Because of the small number of cases, our study had limited power, and the non-statistically significant increased relative risk we observed might reflect the random play of chance. The small number of HF cases we observed was in part due to our restriction of the study population to persons younger than the age of 50, which was done to focus on a younger population identified in a prior report of HF associated with TNF-α
antagonists that included some patients without cardiovascular risk factors [2
]. Our study does not address the risk of HF among older persons or those with different patterns of cardiovascular comorbidities. Additionally, the small number of cases precluded adjustment for potentially important confounders of interest. Another limitation of our work was that TNF-α
exposure (among treated patients) was mentioned in some of the medical records that were reviewed by physicians that confirmed HF (although these physicians did not have access to the pharmacy claims data).
In conclusion, among younger persons with few cardiovascular comorbidities, we observed only a few presumed cases of incident HF and a relatively low absolute risk, even among those exposed to TNF-α antagonists. Particularly, among RA patients, we did find an increased relative risk associated with TNF-α antagonists that was not statistically significant. Confounding by indication or a chance finding may account, in part or whole, for the increased relative risk estimate we observed. A larger cohort and/or additional follow-up time would provide more precise relative risk estimates and permit adjustment for potential confounding.
Rheumatology key messages
- In a cohort of more than 4000 RA and Crohn’s patients younger than 50 yrs, the cumulative incidence of presumed heart failure was low (4 and 1 case per 1000 patients, respectively).
- In RA patients there was an increased relative risk of incident heart failure associated with anti-TNF therapy that was not statistically significant; however, confounding by indication or chance alone could explain this finding.