Combination treatments with two or more antihypertensive drugs are most effective in managing challenging hypertension in patients taking ibrutinib, new research show.

A US study found that patients with prior-hypertension appear to benefit from combination regimens with beta blockers and hydrochlorothiazide, whereas patients with de novo hypertension appear to benefit from ACE inhibitors/angiotensin receptor blockers (ARBs) with hydrochlorothiazide.

Writing in Blood Advances, the US authors said that while Bruton’s tyrosine kinase inhibitors (BTKis) are generally well-tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, targeted drugs such as ibrutinib have the potential to cause new or worsening hypertension that is challenging to treat.

With an absence of guidance on management of BTK-related hypertension, a team of clinicians at the Fred Hutchinson Cancer Center and the University of Washington School of Medicine, analysed data from 196 patients with lymphoid malignancies who were treated with a BTKi and anti-hypertensive drugs and with at least three months of follow up data .

In the study population, 118 patients had prior hypertension, and 78 developed de novo hypertension.  Nearly 90% of patients were taking ibrutinib, with the rest treated with acalabrutinib or other, newer BTKi’s such as zanubrutinib.

The analysis showed that patients in the prior-hypertension group who took beta blockers along with hydrochlorothiazide achieved statistically significant average reductions in mean arterial pressures of about 5 mmHg.

Patients in the de novo hypertension group who took ACE inhibitors or ARBs along with hydrochlorothiazide achieved similar reductions BP (-5.47 mmHg).These regimens also correlated with the greatest percentages of normotensive patients: about 15% of patients in both groups taking beta blockers and hydrochlorothiazide reached a normal blood pressure range (120/80 mmHg or lower).

“To our knowledge, this is the first and only study to examine how to optimally treat high blood pressure in patients receiving ibrutinib,” said senior study author Dr Mazyar Shadman, a haematologist at the University of Washington.

“Our findings strongly suggest that aggressive treatment with certain combinations of antihypertensive medications can achieve significantly reduced blood pressures in this patient population.”

However the study findings do not shed any light on the mechanism by which certain combination regimens were more effective than others or why different combination regimens were most effective in patients with pre-existing and new-onset hypertension, Dr Shadman added.

“But we now have some data that other researchers can analyse to perhaps find answers to these questions,” he said.

Study lead author Dr Laura Samples said several studies have shown that BTKis can cause patients to develop new or worsening high blood pressure, with one study finding this to be the case in over 78% of patients treated with ibrutinib over a median of 30 months.

“Our results reinforce that – in this patient population as in patients with hypertension in general – you need to treat with multiple drugs to achieve successful blood pressure control,” said Dr Samples.

Studies suggest that patients taking newer BTKi agents still face an increased risk of major adverse cardiovascular events, although the risk may be lower than that of ibrutinib, she added

“Given that increased blood pressure is a “class effect” of treatment with BTKis, both doctors and patients need to be aware of this risk and patients’ blood pressure should be monitored regularly so that treatment can begin immediately when an increase is detected,” Dr Samples said.

The  study funded by AstraZeneca.