The CACHE Study: Coronary Artery Care in HaEmophilia

Background and Rationale

Haemophilia, ageing and cardiovascular disease It is only relatively recently, due to the development of both effective and safe replacement therapies, that there is an aging population with haemophilia. This represents new challenges with respect to managing comorbidities. Cardiovascular disease (CVD) is the leading cause of death globally in the general population, and as people with haemophilia (PWH) age they are also at risk of developing CVD which poses particular challenges due to the opposing risks of bleeding, from haemophilia and antithrombotic treatments, versus thrombosis. Better understanding of the risks of atherosclerosis in PWH is crucial in order to best support aging PWH; and it has been identified as a research priority by patients and healthcare professionals.

Although mortality from cardiovascular disease in PWH has historically been about 40% less than the general population, it remains unclear whether this is because people with haemophilia develop atherosclerosis more slowly than the general population or whether deficiency of FVIII/FIX protects from formation of an occlusive thrombus at time of atherosclerotic plaque rupture. As FVIII is produced and stored within endothelial cells lining the blood vessels and FIX is produced in the liver, it may also be that FVIII and FIX deficiencies have different effects on the rates of atherosclerosis.

The most informative studies of atherosclerosis in PWH to-date used ultrasound to measure carotid and femoral intima-media thickness and computed tomography (CT) to derive coronary artery calcium scores. The first study measured carotid and femoral intima-media thickness (IMT) and brachial flow-mediated dilatation (FMD) as markers of atherosclerosis and endothelial dysfunction respectively in 51 obese PWH, and 42 obese and 50 matched non-obese male patients. All the PWH had haemophilia A (33% severe, moderate 16%, mild 50%), HIV was excluded, and the mean age was 50 +/-13 years. Carotid IMT was increased in obese as compared with non-obese subjects, but no difference was found in mean carotid and femoral IMT between obese PWH and obese control individuals. Thirty-five per cent of the obese PWH and 29% of the obese controls had an atherosclerotic plaque, irrespective of the severity of haemophilia. Brachial FMD was comparable between obese PWH and obese controls. The second study evaluated the presence and extent of atherosclerosis by coronary artery calcification score (CACS) derived from computed tomography and carotid IMT in 69 PWH (51 haemophilia A, 18 haemophilia B; 40% severe, 11% moderate, 49% mild). This again showed that CACS and carotid IMT were similar to controls and that the extent of atherosclerosis was related to traditional cardiovascular risk factors. Although these studies suggest PWH develop atherosclerosis at a similar rate to the general population; they are severely limited by the quality of the imaging techniques, patient numbers and relatively young patient age (average 50 years).

Cardiology guidelines recommend using a risk score to calculate cardiovascular risk over time and engaging patients in discussing modifiable risk factors. These scores have been used in PWH. A Dutch/UK cohort used both the QRISK(R)2 and SCORE algorithms. The predicted 10-year QRISK(R)2 risk was significantly higher in PWH than in the general population (8.9 vs. 6.7%), indicating more unfavourable cardiovascular risk profiles; and the increased risk became apparent after the age of 40 years. In contrast a study of 100 PWH in Europe compared to 200 aged-matched controls, found no significant difference in the 10-year cardiovascular mortality risk >10% between PWH and controls using SCORE. Other studies have looked at individual cardiac risk factors and PWH had higher rates of hypertension than expected for the general population. Critically whether the cardiac risk algorithm conveys the same actual CVD risk and is valid in PWH is not known.