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Anti-TNF and Cardiovascular Disease


Rare but serious adverse events are difficult to measure in randomised trials. When rates of such events are below 1 in 100, and especially 1 in 1000, conventional trials of a few hundred patients or fewer are usually insufficiently large for even a single event to reliably be captured. Consequently we rely on observational studies.

Prospective evaluations of patients treated with new medicines in registers are unusual. Bandolier 104 discussed one such for anti-TNF therapy in rheumatoid arthritis: it gave the same efficacy result as meta-analysis of randomised trials. A new report [1] follows up, but rather than reporting an unexpected adverse event, it records an unexpected benefit.


The study was based in southern Sweden, on a register of patients treated with anti-TNF agents, and a community-based cohort within the same geographical area, largely before the introduction of the agents. There were, therefore, two cohorts, those exposed and those not exposed to anti-TNF therapies. The exposed cohort was based on a population of 1.3 million, and included all patients with rheumatoid arthritis treated with anti-TNF agents, between early 1999 and end 2001. The unexposed cohort was from the southern Swedish city of Malmö with a population of 0.3 million, from mid-1997.

Patients in the cohorts had to be free of pre-existing cardiovascular disease. Outcome was a new cardiovascular disease event during the study period, without a previous event in the preceding 10 years. Information on cardiovascular events came from national discharge and death registries, in which discharge diagnoses and causes of death have been verified as accurate.


Patients in both groups were mainly (76%) women, with an average age of 58 years. Those treated with anti-TNF agents tended to have greater initial disease severity in terms of global assessment, pain, and health assessment scores, and a much higher proportion of treated patients had received previous prednisolone treatment (75% compared with 22%) and more disease modifying drugs.

There were fewer cases of first cardiovascular disease event with anti-TNF treatment (Table 1), occurring in 1 in 71 exposed patients compared with 1 in 29 unexposed. The age, sex, and disability adjusted incidence rate was significantly reduced, with a relative risk of 0.5 (0.3 to 0.9). Several different analyses, for instance over the time the cohorts overlapped, or by various markers of severity, reached much the same result, as did excluding some cardiovascular disease endpoints, like heart failure.

Table 1: First cardiovascular disease events and mortality in rheumatoid arthritis patients exposed and not exposed to anti-TNF agents

Not exposed
Patient years
Cardiovascular disease
Cases (n)
Age, sex incidence (per 1000 pt years)
Cardiovascular death
Cases (n)
Age, sex incidence (per 1000 pt years)
All-cause death
Cases (n)
Age, sex incidence (per 1000 pt years)

There were also fewer cardiovascular deaths (Table 1). Age and sex adjusted rates were 1 in 450 for exposed, and 1 in 200 for unexposed). All-cause deaths were also lower, with age and sex adjusted rates of 1 in 310 and 1 in 84 respectively. The number of deaths was small, though.


This is good news. Anti-TNF agents, while expensive, produce excellent results in appropriate rheumatoid arthritis patients. The implication that they probably produce additional, perhaps unexpected, benefits, is welcome. The figures suggest that anti-TNF therapy for one year reduces new cardiovascular events by an absolute 2%, or a one-year NNT of 50. If that were maintained over the longer term, a 10-year NNT of 5 would be better than statins in someone with a 30% 10 year cardiovascular risk. Moreover, the authors show that the standardised mortality rate with anti-TNF treatment was the same as that for the background population of Malmö.

The problem is numbers. We have only 13 cases of cardiovascular events with TNF therapy, and this, however good, is an observational study. Without supporting evidence we must be cautious about extolling this potential benefit.

It is interesting to reflect on the reaction to these results had they been the other way around, and we were reporting more cardiovascular events, rather than fewer. Caution should still have been the watchword, but what the reaction would have been, despite the tremendous benefits of anti-TNF therapy, is a different question for another day.


  1. LT Jacobsson et al. Treatment with tumor necrosis factor blocker is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. Journal of Rheumatology 2005 32: 1213-1218.

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