Lipoprotein apheresis may have new role in patients with refractory angina

Initial investigation of patients with suspected coronary heart disease (CHD) using functional imaging - rather than guideline-directed care - resulted in significantly less unnecessary angiography, according to results of the CE-MARC 2 trial.

The findings, presented in a Hot Line session at ESC Congress 2016, and published simultaneously in JAMA, could have an important impact on referral rates for invasive coronary angiography, and potentially healthcare costs, said lead investigator John Greenwood, PhD, from the University of Leeds, in Leeds, United Kingdom.

"Rates of invasive angiography are considered too high among patients with suspected coronary heart disease," explained Professor Greenwood.

"Our findings show that both cardiovascular magnetic resonance (CMR) and myocardial perfusion scintigraphy (MPS) significantly reduced rates of unnecessary angiography compared to guideline-directed care, with no penalty in terms of major adverse cardiovascular events (MACE). This suggests that functional imaging should be adopted on a wider basis, even in high-risk patient subgroups."

The Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC 2) trial included 1,202 patients with suspected CHD from six UK centers.

The patients were randomised to functional imaging-based investigation with either CMR (n = 481) or MPS (n = 481), or to guideline-directed investigation (n=240) based on National Institute for Health and Care Excellence (NICE) guidelines.

In this latter group, those with a pre-test likelihood of 10%-29% (meaning low risk for CHD based on age, gender, symptom characteristics, and clinical history) were scheduled for cardiac computed tomography (CCT), those with a pre-test likelihood of 30% to 60% (intermediate risk) were scheduled MPS, and those with a high pre-test likelihood were sent directly to coronary angiography.

The primary end point was unnecessary coronary angiography within 12 months, (defined by absence of significant stenosis measured by fractional flow reserve or quantitative coronary angiography), with secondary end points of MACE, and positive angiography within this same time period.

Overall, 22% of the study population underwent coronary angiography within 12 months, with unnecessary angiograms occurring in 28.8% of the NICE guidelines group, 7.5% of the CMR group, and 7.1% of the MPS group, reported Professor Greenwood.

The adjusted odds ratio of unnecessary angiography for the CMR group versus the NICE guidelines group was 0.21 (95% CI, 0.12-0.34; P < .001), with no statistically significant difference between the CMR and MPS groups.

Between the three strategies, there was no difference in short-term MACE or positive angiography rates.

"Worldwide, MPS is the most commonly used test to assess suspected CHD, but CMR is increasingly recognized as having high diagnostic accuracy and prognostic value," noted Professor Greenwood. "Although the results of CE-MARC 2 showed no difference between the CMR and MPS strategies in terms of unnecessary angiography rates, our original CE-MARC study showed that CMR had a higher diagnostic accuracy compared to MPS (Lancet 2012; 379(9814):453-460) and was also a stronger predictor of risk for MACE (Annals of Internal Medicine 2016; 165(1):1-9)."

He concluded that "these results show that a broader use of functional imaging (CMR or MPS), in low, intermediate and high risk patient groups, could reduce the rates of invasive angiography that ultimately show no obstructive coronary disease. In addition, CE-MARC and CE-MARC 2 further support the role of CMR as an alternative to MPS for the diagnosis and management of patients with suspected CHD." Lipoprotein apheresis, a therapy normally used to filter excess cholesterol from the blood of patients with familial hypercholesterolemia, may have a new role in patients with refractory angina.

New results reported during a Hot Line session at ESC Congress 2016 showed the extracorporeal treatment resulted in significant improvements compared to sham therapy in patients who had refractory angina along with raised levels of lipoprotein(a).

"Angina which is refractory to both medical therapy and revascularisation is a debilitating condition that is increasing in frequency, and there is a pressing need for novel treatments for these patients," said lead investigator Tina Khan, MRCP, from Royal Brompton and Harefield NHS Trust and Imperial College in London, United Kingdom.

The apheresis procedure study was conducted at Harefield Hospital, under the Directorship of the Principal Investigators Mahmoud Barbir, FRCP and Dudley Pennell, MD.

"These patients continue to suffer with troublesome angina despite optimal medical therapy, as well as surgical and/or percutaneous coronary revascularization, and available treatment options are limited," she added.

"Our trial provides the first evidence that lipoprotein apheresis leads to improvement among these patients in the primary endpoint of myocardial blood flow, as measured by myocardial perfusion reserve, as well as the secondary endpoints of exercise capacity, angina symptoms, quality of life and atheroma burden. Therefore this treatment approach could improve the cardiac health and lives of such patients."

Lipoprotein(a) - abbreviated as Lp(a) - is similar in structure to LDL cholesterol, except for an additional protein attached called apolipoprotein(a). Raised Lp(a) is a strong risk factor for coronary heart disease and may be prevalent in patients with refractory angina.

Studies suggest that elevated Lp(a) may promote atherosclerosis and reduce blood flow through the heart (myocardial perfusion), but there is currently no effective pharmacologic treatment yet approved to treat elevated Lp(a) - and it is essentially resistant to conventional lipid-lowering treatment with statins, said Dr. Khan.

However, Lp(a) can effectively lowered with lipoprotein apheresis.

The prospective randomised, sham controlled, blinded, cross-over study included 20 patients with refractory angina and elevated Lp(a) levels above 500mg/L.

Participants were randomised to weekly lipoprotein apheresis or sham treatments for 3 months and then crossed over for another 3 months, with a one-month washout period in-between.

The primary outcome, measured with cardiac magnetic resonance imaging, was Myocardial Perfusion Reserve (MPR) - which is the ratio of the myocardial blood flow at stress versus rest after three months of lipoprotein apheresis, compared to baseline.

The study showed a significant increase of 0.63 in MPR after apheresis treatment compared to sham (P<0.001).  Specifically, MPR increased from 1.45 to 1.93 with apheresis, but did not change significantly after sham.

Secondary endpoints of carotid wall volume and distensibility were also improved after apheresis but not sham, as were exercise capacity, symptoms of angina, and quality of life scores, said Dr. Khan.

In terms of symptoms, there were significant improvements after apheresis but not sham in 4 out of 5 domains in the Seattle Angina Questionnaire (SAQ), including the:

*Physical limitation score (median change of 27.8 vs -4.2);

*Angina stability score (mean change of 17.5 vs -3.75);

*Angina frequency score (mean change of 35.0 vs -5.0);

*Quality of life score (mean change of 25.8 vs 4.6).  

On the fifth domain, SAQ treatment satisfaction score improved slightly by 6.25 during apheresis vs 0.0 or no change during sham.

Similarly, physical component scores of quality of life assessed by the Short Form (SF)-36 Questionnaire also improved significantly after apheresis but not sham.

"Our study is the first randomised controlled trial to assess the impact of lipoprotein apheresis in patients with refractory angina and raised Lp(a), in the absence of significantly raised LDL cholesterol," said Dr. Khan.

"These findings suggest that lipoprotein apheresis provides significant clinical benefit to patients with refractory angina in the context of raised Lp(a), representing a much needed novel treatment option for this therapeutically challenging patient cohort."

Source: European Society of Cardiology (ESC)