Table 1

Insights from recent randomised controlled trials specific to patients with NOCAD and CMD.

Trial, journal and year	Patients with NOCAD (n)	Pertinent results in patients with NOCAD	Take home messages for NOCAD
FAME-2, NEJM, 201213	332/1220 (27%) of patients had an FFR >0.80	Similar CCS angina class compared with FFR <0.80. Similar levels of silent ischaemia compared with FFR <0.80. MACE rate of 9% in 2 years.	Patients with NOCAD have similar symptom burden to patients with CAD. Patients with NOCAD have a high MACE rate.
PROMISE, NEJM, 201536	4477/4996 (90%) of patients in the CTCA group had a ‘negative’ result	89% of patients had typical or atypical angina in both groups. Only 10% of patients in the CTCA group had angina attributable to CAD.	A large proportion of anginal symptoms are attributable to NOCAD in patients with an intermediate PTP of CAD.
SCOT-HEART, Lancet, 201537	1326/1778 (75%) in the CTCA groups had anatomical NOCAD	CTCA-guided therapy resulted in a reduced diagnosis of angina due to CAD, prompting alteration of therapy in this group, and deterioration in QoL and symptoms. Patients in the CTCA group with a change in diagnosis, either confirming obstructive CAD or excluding CAD had the greatest improvement in symptoms, while those with non-obstructive CAD had the least improvement in symptoms.	In a population with high predicted 10-year CHD risk, NOCAD is common. Defining NOCAD anatomically (instead of with FFR) may explain the poorer outcomes in the non-obstructive CAD group. Inappropriate cessation of antianginal therapy in patients with NOCAD with CMD may have attenuated symptom improvement derived by identifying CAD and revascularisation leading to symptom neutrality when adopting a CTCA-guided approach.
CE-MARC 2, JAMA, 2016 38	139/265 (52%) of patients who underwent angiography had NOCAD	All 1202 patients had angina with 401 (33%) having typical angina. A minority of patients had a positive non-invasive test (12.4% in the CMR group, 18.2% in the MPS group and 13.4% in the NICE guideline group).	Adhering to NICE guidelines results in a frequent diagnosis of NOCAD. The rate of ‘unnecessary angiography’ was nearly double in women, compared with the rate in men.
ORBITA, Lancet, 201739	57/200 (29%) of patients had an FFR >0.80	In a sham-placebo trial, PCI was found to be equivalent to OMT in providing symptom relief. Patients with angina and FFR >0.80 also underwent PCI and may have diluted effects between the groups.	NOCAD is common among lesions judged to be visually severe. Differences in microvascular physiology is postulated to have contributed to inconsistent benefits of PCI.
ISCHAEMIA and CIAO-ISCHAEMIA substudy, tba40	5179 patients with moderate ischaemic burden have been randomised to an invasive approach versus OMT (ISCHAEMIA trial)	A proportion of patients with moderate-to-severe ischaemia on stress testing have NOCAD (enough to justify forming the CIAO-ISCHAEMIA substudy).	INOCA is an increasingly recognised entity that warrants specific management.

CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; CFR, coronary flow reserve; CMR, cardiovascular magnetic resonance; CTCA, CT coronary angiography; FFR, fractional flow reserve; INOCA, ischaemia with no obstructive coronary disease; MACE, major adverse cardiovascular events; MPS, myocardial perfusion scintigraphy; NICE, National Institute for Health and Clinical Excellence; NOCAD, non-obstructive coronary artery disease; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; PTP, pretest probability.