LIVERPOOL, ENGLAND – A new analysis of data from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register confirms that anti–tumor necrosis factor treatment decreases patients’ risk for heart attack when compared with treatment with traditional, nonbiologic disease-modifying antirheumatic drugs, but a lower level of inflammation may not be the mechanism of action.
In the latest analysis, the risk of myocardial infarction was reduced by 40% if patients had been treated with an anti–tumor necrosis factor (anti-TNF) drug rather than a nonbiologic disease-modifying antirheumatic drug (nbDMARD) (adjusted hazard ratio, 0.6).
But this effect was not the result of a reduction in the severity of inflammation, said researcher Dr. Audrey Low of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis (BSRBR-RA) Register is run. Nevertheless, the effect could still relate to attributes of these drugs themselves or better overall disease control, she and her coworkers reported at the British Society for Rheumatology annual conference.
"It is now well known that our patients with rheumatoid arthritis are at increased risk of cardiovascular disease," Dr. Low observed, adding that the risk of both cardiovascular morbidity and mortality is around 50% higher than in the general population. "In particular, the risk of MI [myocardial infarction] is increased," she noted.
Inflammation is thought to play an important role in the development of both atherosclerosis and rheumatoid arthritis, and thus dampening down the inflammatory response with anti-TNF drugs could potentially modify the elevated cardiovascular risk seen in RA patients.
Previously, Dr. Low reported that the risk of MI was lowered by 30% in patients treated with anti-TNFs versus nbDMARDs. The current study looked more deeply into the possible relationship, linking BSRBR-RA Register data to those in the Myocardial Ischaemia National Audit Project (MINAP), a large MI data set derived from all hospitalizations for heart attack in England and Wales. MINAP was established in 1999, 2 years before the BSRBR-RA Register, and it collects around 90,000 records of possible MI per year. As of 2012, MINAP consisted of more than 1 million records.
The aims of the current analysis, which included 14,258 patients with active RA, were to first look at the incidence of MI in patients treated with anti-TNFs (n = 11,200) versus nbDMARDs (n = 3,058), and then to see if the severity of MI was influenced by biologic treatment. The analysis included all patients who started treatment with one of three established anti-TNFs (etanercept, infliximab, and adalimumab) and were recruited into the BSRBR-RA Register between 2001 and 2008. Patients with prior cardiovascular disease were excluded.
To verify the occurrence of MI, data from the BSRBR-RA Register were linked to data from MINAP using patients’ forenames, surnames, date of birth, National Health Service number, postal code, and gender. Events occurring in the same 30-day time window in both data sets were considered the same event. MIs were then verified using criteria set by the American Heart Association and the European Society for Cardiology, with additional criteria of thrombolysis, angioplasty, and MI listed as the underlying cause of death on death certificates, based on the World Health Organization’s International Classification of Diseases, version 10.
A total of 252 first MIs were analyzed, of which 194 occurred in anti-TNF–treated patients at a median follow-up of 5.3 years and 58 occurred in those treated with nbDMARDs at a median follow-up of 3.5 years. The corresponding crude incidence rates were 3.5 and 5.6 per 1,000 patient-years.
"Looking at the MI severity, we only analyzed those MIs that had MINAP-associated data," which was just over half of the MIs (n = 143), Dr. Low said. While the absolute levels of three cardiac enzymes measured – peak troponin I, peak troponin T, and peak creatinine kinase – were higher in the anti-TNF cohort, compared with nbDMARDs, there were not enough events in each group to achieve statistical significance.
There were also no differences between the treatment groups in terms of other cardiac measures of severity, including the phenotype of MI (ST- vs. non-ST elevated), cardiac arrest, and length of hospitalization.
"So the second conclusion is that severity and post-MI mortality do not appear to be influenced by anti-TNF therapy," Dr. Low said.
BSR president Dr. Chris Deighton, who chaired the plenary session in which the findings were presented, noted that there seemed to be a high proportion of patients in the anti-TNF arm who were also treated with steroidal or nonsteroidal anti-inflammatory drugs (NSAIDs) at enrollment. Perhaps if the anti-TNFs were working well, then any reduction in the use of these other drugs over time might have had a confounding effect on the MI risk.