The Novel Use of Transcutaneous Electrical Nerve Stimulation in Patients with Angina and Non-Obstructive Coronary Arteries; a Pilot Study

In patients with angina pectoris undergoing a coronary angiography (CAG) up to
40% do not have obstructive coronary artery disease (CAD) (1). The majority of
patients with no obstructive CAD are women with a frequency of up to 70%
compared to 50% in men (2) These patients are diagnosed as having angina and
non-obstructive coronary arteries (ANOCA) (3). There are two endotypes of
ANOCA. The first endotype is microvascular angina (MVA) caused by a combination
of structural microcirculatory remodelling and functional arteriolar
dysregulation, also called coronary microvascular dysfunction (CMD) (2). The
second endotype is vasospastic angina (VSA) caused by epicardial coronary
artery spasm that occurs when a hyper-reactive epicardial coronary segment is
exposed to a vasoconstrictor stimulus (2). A subgroup of patients with ANOCA
have both CMD and epicardial coronary artery spasm. Both endotypes of ANOCA are
associated with significantly greater one-year risk of myocardial infarction
(MI) and all-cause mortality (4), have a significantly impaired quality of life
(5) and have a high health care resource utilisation (6).

The 2019 ESC Guidelines on the management of chronic coronary syndromes give a
Class IIa (Level of evidence B) recommendation to perform guidewire-based
coronary function testing (CFT), consisting of coronary flow reserve (CFR) and
index of microcirculatory resistance (IMR) measurements, in patients with
persisting symptoms and no obstructive CAD (7). The same guidelines give a
Class IIa (Level of evidence B) recommendation to also perform intracoronary
acetylcholine testing to assess the presence of coronary vasospasm in this
patient population (7). By performing CFT a definitive diagnosis of ANOCA and
the specific endotype can be made. MVA is diagnosed based on a fractional flow
reserve (FFR) > 0.8, CFR <2.0 and IMR >= 25 (2). VSA is diagnosed based on FFR >
0.8, CFR >= 2.0, IMR < 25 and during acetylcholine testing a >= 90% diameter
reduction, angina pectoris as well as ischaemic electrocardiographic (ECG)
changes (2). The use of CFT followed by patient tailored treatment based on CFT
findings has been shown to improve angina severity in patients with ANOCA (8).

The current treatment for ANOCA consists of three aspects. The first aspect is
managing lifestyle factors such as weight management, smoking cessation and
exercise. The second aspect is managing known cardiovascular risk factors such
as hypertension, dyslipidaemia and diabetes mellitus. And the third aspect is
antianginal medication. In both endotypes ACE inhibitors or angiotensin II
receptor blockers should be considered. In MVA the antianginal medication that
can be used are betablocker, calcium channel blocker, nicorandil, ranolazine,
ivabradine and/or trimetazidine (2). In VSA calcium channel blocker,
long-acting nitrate and/or nicorandil can be initiated as antianginal therapy
(2). Despite these treatment option approximately 25% of ANOCA patients have
refractory angina symptoms (2).

As stated in the 2020 consensus statement of the ESC on ischaemia with
Non-Obstructive Coronary Arteries (INOCA) there is a lack of in-depth knowledge
with further research urgently needed to develop innovative therapies to better
manage this serious condition (2). A possible treatment modality for ANOCA
patients with persisting symptoms is spinal cord stimulation (SCS) or
transcutaneous electrical nerve stimulation (TENS) as mentioned in the Dutch
NVVC guideline on ANOCA (9-11). Previous research has shown that SCS improves
the time until angina and ischaemia, leads to significantly less angina
pectoris episodes and also leads to a significant improvement in quality of
life (12-15). An important side note is that the afore mentioned studies were
performed during the 90s in patients with coronary syndrome X. Coronary
syndrome X was defined as patients with typical exercise-induced angina,
positive exercise testing and normal coronary arteries. This is most likely a
more heterogeneous group of patients than the contemporary ANOCA patients as
invasive CFT was not yet available at the time these
studies were performed. However these findings do suggest that SCS and/or TENS
could be a possible treatment modality for patients with ANOCA. The aim of this
pilot study is to investigate whether treatment with TENS during a one month
period leads to a significant reduction of angina pectoris and therefore a
significant improvement in quality of life in patients with proven ANOCA,
encompassing the VSA endotype.

To evaluate the effect of transcutaneous electrical nerve stimulation (TENS) in
patients with ANOCA on the change in the summary score of the Seattle Angina
Questionnaire (SS SAQ) after 1 month treatment with TENS, compared to baseline.

Prospective, single-arm, open label, single center pilot study

All patients who participate in this study will receive TENS for a duration of
4 weeks.

Patients who are asked to participate in this pilot study will receive TENS
during a one month period. TENS is a treatment modality that has been broadly
applied in patient with chronic pain syndromes. A recent meta-analysis has
shown that no serious adverse events are associated with use of TENS and
adverse events that occurred were skin irritation, tenderness and TENS
discomfort which occurred infrequently (18). In addition TENS has been
described as a possible treatment modality for ANOCA patients in the recent
Dutch NVVC Guidelines on ANOCA, but with the side notes that results up to date
differ (11). This shows that TENS could be an effective and safe treatment
modality in a group of ANOCA patients who have persistent and disabling angina
pectoris despite OMT, but additional research is required. The risks of this
study are small and the possible benefits for the patient could be large with a
reduction of symptoms and an improvement in quality of life. Furthermore there
are no other treatment modalities currently available for this patient
population. In conclusion this TENS pilot study is safe, with a low risk and
large benefit for the patient.