Statins Linked to Reduced Mortality in Ankylosing Spondylitis

Janis C. Kelly

July 20, 2017

Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) might be one tool for reducing the 60% increase in premature mortality associated with ankylosing spondylitis (AS), according to data from a population-based cohort study. However, clinicians were warned not to overgeneralize from these findings.

Amar Oza, MD, from the Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, and colleagues report their findings in an article published online July 11 in the Annals of the Rheumatic Diseases.

The researchers used a UK general population database, correcting for potential confounders, to show that all-cause mortality was 16.5/1000 person-years (PY) for statin initiators vs 23.8/1000 PY for those not taking statins, for a hazard ratio of 0.63 (95% confidence interval, 0.46 - 0.85). There were 1430 patients in each group.

"Our results were clinically significant. We found an all-cause mortality reduction of 37% for patients with ankylosing spondylitis initiated on statin therapy, which was higher than that seen in the general population [taking statins]," Dr Oza told Medscape Medical News.

"I was surprised at the magnitude of all-cause mortality reduction in our study. Large population-based studies have shown an increased risk of all-cause mortality in rheumatoid arthritis and in AS patients. While a recent study of [rheumatoid arthritis] patients on statins showed an all-cause mortality reduction similar to the general population, our study in AS patients had a greater mortality reduction, at 37%."

The study population included patients older than 20 years (median age, 61.7 years for statin users, 57.3 years for nonusers). All had a recorded diagnosis of AS between January 1, 2000, and December 31, 2014. To account for confounding, the researchers created a propensity score on the basis of disease duration, body mass index, lifestyle factors, comorbidities, and medication use.

When they compared the unmatched AS cohorts, patients who began statins had a 43% higher risk for mortality than those who did not take statins. To account for differences that might have been a result of confounding by indication, the researchers matched cohorts by propensity scores, which showed 96 deaths in the 1108 patients who initiated statins and 134 deaths among matched noninitiators. Mortality rates were 16.5 and 23.8 per 1000 PY, respectively. The absolute mortality rate difference was 7.3 deaths/1000 PY.

The authors note that the association between statins and reduced mortality "was independent of age, sex, [body mass index], socioeconomic status, relevant comorbidities, cardiovascular medication use, total cholesterol levels and healthcare utilisation."

The authors explain, "As patients with AS are affected by systemic inflammation and are at a higher risk for [cardiovascular disease], the dual anti-inflammatory and lipid-lowering effects of statins may be more pronounced than in the general population.... To our knowledge, this is the first study to find a potentially substantial mortality benefit of statin use in patients with AS."

"Our findings raise a number of questions: Why would there be a greater benefit in AS than in other inflammatory diseases or the general population? Can these results be replicated in a rheumatologic cohort with variables like disease activity and biologic use included? What is the pathophysiologic basis for these findings?" Dr Oza said.

Replication in other patient populations will be required to firmly establish the mortality benefits of statins in patients with AS. Meanwhile, Dr Oza said that from a clinician's standpoint, these data suggest a role for careful screening of patients with AS for cardiovascular risk factors, adding, "[a]s more evidence arises, the guidelines will likely require modification." As in patients without AS, statins may be undesirable for patients with AS who have known liver or muscle comorbidities.

AS expert Nigil Haroon, MD, PhD, was similarly cautious. Dr Haroon, who was not involved in the study, is a rheumatologist and physician scientist working at the University Health Network, Toronto, Ontario, Canada. He is also an assistant professor of medicine and rheumatology at the University of Toronto.

"This is a nicely done study but is not generalizable to all patients with AS. Although I would love to see data for the benefit of statins for primary prophylaxis in AS patients, I do not think we can recommend this at this time," he told Medscape Medical News.

Dr Haroon pointed out that the mean age of patients in the study was more than 60 years at baseline, whereas the usual age of patients with AS at presentation is around 30 to 40 years, at which time overall cardiovascular risk is quite low.

"Moreover, at baseline, over 50% had hypertension, 20% had diabetes, and 10% had ischemic heart disease. I am not sure if the benefits reported in this study would hold true for younger patients with no history of ischemic heart disease/prior heart attacks/strokes," he said.

Deborah Symmons, MD, professor emerita, Centre for Musculoskeletal Research, School of Biological Sciences, University of Manchester, United Kingdom, also added a note of caution: "I think that this is a 'sound' analysis. Unfortunately, the authors have only looked at all-cause mortality and not at cause-specific (in this case, cardiovascular) mortality. We would mainly expect statins to impact cardiovascular mortality," Dr Symmons told Medscape Medical News. She was not involved in the study.

"My understanding is that, in general, statin trials have shown an approximately one third reduction in major cardiovascular events (a term which includes cardiovascular deaths and nonfatal myocardial infarction and stroke) regardless of the patient group studied. This one third reduction is in comparison to what the same group of people would have experienced if they had not been exposed to statins. If patients start with a low risk, then the one third reduction may not be cost-effective to achieve, as it is a very small number of lives saved for the number of patients needed to treat. In patients with a high background risk, this one third reduction represents a substantial number of lives saved," Dr Symmons explained.

"In this study, the authors have shown a one third reduction in all-cause mortality in a group of patients (mainly middle-aged men) in whom the major cause of death would be expected to be cardiovascular. Therefore, the relative reduction seen with statins is higher than, for example, a group of elderly patients of both sexes, in which cardiovascular deaths might only account for about one fifth of all deaths. In other words, I think that the authors have demonstrated that statins work as well (but not better) in patients with [AS] as they do in any other patient group," Dr Symmons said.

"These data support the ongoing use of statins as they are currently used in the UK population for primary prevention. Statins in this population will have been prescribed to patients with a high background risk of [cardiovascular disease,] as assessed using the UK risk calculator that was in use at the time of first prescription," Dr Symmons added.

"It is sometimes argued that patients with conditions such as AS are systematically excluded from clinical trials of statins, and so we do not know if statins work in AS. This study shows that they do work, but it does not provide any evidence for extending their use in AS beyond those patients who would have received them according to national guidelines for the general population. We can say that, as patients with AS plus recognized indications for statins benefit from statin treatment, it is important to screen patients with AS regularly to ensure that those who should be on a statin are identified," she explained.

The authors and Dr Haroon have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online July 11, 2017. Abstract

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