Vasospastic angina treatment by Endothelin Receptor Antagonism; a proof of concept study

A considerable proportion of patients with typical anginal complaints have no
or only mildly obstructive coronary artery disease as diagnosed by coronary
angiography (CAG). This disease is called non-obstructive artery disease
(NOCAD). While women have a larger burden of many cardiovascular risk factors
than men and have a similar or even higher prevalence of angina, fewer cases of
obstructive coronary artery disease (OCAD) are observed in women. Women with
NOCAD are at increased risk for cardiovascular events compared to women with
comparable CAG outcome, but without symptoms and have a worse prognosis
compared to men with NOCAD. These findings underscore clinically relevant sex
differences in the pathophysiology of CAD. The pathophysiology of NOCAD remains
unresolved, but includes vasospasm of the epicardial coronary arteries and
impaired function of the microcirculation (microvascular dysfunction (MVD)).
Prinzmetal et al. were the first to describe this variant form of angina
pectoris which occurred at rest, was associated with ST-segment elevation on
the surface ECG and was relieved by administration of nitroglycerin. Their
hypothesis that coronary spasm was the cause of this syndrome was later
confirmed using coronary angiography. Another cause of myocardial ischemia in
patients without fixed obstructive coronary artery disease, is microvascular
dysfunction. Coronary spasm and microvascular dysfunction comprise a spectrum
of macrovascular and microvascular coronary disease characterized by
endothelial dysfunction and abnormal vasodilatory reserve. This form of
coronary artery disease is particularly prevalent among middle-aged women, and
pharmacological treatment options are a large unmet clinical need in this
patient population.
Endothelin (ET)-1 is a potent vasoconstrictor peptide produced by vascular
endothelium which plays an important role in cardiovascular regulation. It is
becoming increasingly clear that an imbalance between ET-1 and nitric oxide,
the most prominent vasodilator, is a characteristic of endothelial dysfunction
and is important in the progression of vascular disease. The production of ET-1
is stimulated in a variety of different cell types under the influence of
cardiovascular risk factors and during the development of cardiovascular
disease. ET-1 is present in human coronary atherosclerotic plaque. Among
patients with coronary artery disease, circulating ET-1 levels were associated
with the extent and severity of coronary stenoses. Based on these observations
and the biological effects of ET-1, including vasoconstriction,
pro-inflammatory actions, mitogenic and proliferative effects, stimulation of
free radical formation and platelet activation, ET-1 has been implicated as an
important factor in the development and progression of vascular dysfunction and
cardiovascular disease. ET-1 levels have been shown to be elevated among
patients with vasospastic angina. In addition, ET-1 levels are associated with
impaired coronary vasodilatory response. Among patients with coronary artery
disease, intracoronary administration of the endothelin receptor antagonist
(ERA) bosentan was shown to induce coronary vasodilatation. In addition, two
case reports (including one from VU medical center) have documented the
beneficial effects of bosentan in the treatment vasospastic angina.
Bosentan is an ERA with affinity for both the ETA- and ETB-receptor. Treating
coronary vasospasm or microvascular dysfunction is conceptually even more
interesting with selective ETA-receptor blockers that leave the ETB-receptor
and its downstream denominator nitric oxide relatively unopposed. In vitro, the
novel ERA macitentan is 100x more selective for ETA-receptor than ETB-receptor.
We hypothesize that treatment with macitentan reduces the frequency and
severity of anginal complaints among patients with clinically defined
vasospastic angina.

To determine whether VSA treatment with the novel ERA macitentan reduces the
frequency and severity of anginal complaints among patients with clinically
defined VSA. To determine side effects related to treatment with macitentan in
patients with VSA.

Pilot proof-of-concept, multicenter, randomized, cross-over trial. The trial is
double-blind placebo-controlled.

The trial is cross-over placebo controlled. Patients will recieve placebo for 4
weeks and macitentan for 4 weeks while on background (standard) medication. The
order of placebo or macitentan is left to randomisation.

Details of medical history, risk factors, Seattle Angina Questionnaire, WHO
functional status will be recorded at baseline and follow-up. The number of
office visits will be 6 times: at baseline (Visit1), at 4 weeks (Visit 2), at 8
weeks (Visit 3), at 10 weeks (visit 4), at 14 weeks (Visit 5), end at 16 weeks
(Visit 6). Visits 1, 2, 4, 6 will take each about 30-45 minutes: medical
history, risk factors, Seattle Angina Questionnaire, WHO functional status
(15-30 minutes), electrocardiogram (5 minutes), laboratory analysis (10
minutes, 9ml). All investigations are part of regular medical care according to
international guidelines and the current standardized protocol being used in
the Academic Medical Center. Most commonly reported adverse reactions of
macitentan are nasopharyngitis, pharyngitis, influenza, nasal congestion,
bronchitis, decrease in leucocytes and thrombocytes, headache, edema, fluid
retention, urinary tract infection. The majority of these reactions are of mild
to moderate intensity and are manageable with symptom relieve treatment. Less
frequent side effects are liver function abnormalities, however, the study
medication is given for 4 weeks only. The use of other (non)-cardiac medication
by the study population during this study is allowed, and is recorded.