High blood pressure - PATHWAY

The clinical question

High blood pressure affects 1 in 3 people in the UK. It isn’t usually something that you can feel or notice, but it increases your risk of developing coronary heart disease or having a stroke. Lifestyle changes such as cutting down on salt in your diet can help to reduce high blood pressure. But doctors may also need to prescribe medication to control it. 

People with high blood pressure are commonly prescribed up to three types of different medications to lower their blood pressure:

• An ACE inhibitor or angiotensin receptor blocker (ARB), which reduce the effects of a hormone that causes blood vessels to constrict.
• A calcium-channel blocker, which reduces this constriction by limiting how much calcium enters blood vessel cells.
• A diuretic, sometimes called a 'water tablet'. This increases the amount of salt and water lost through urine. 

However, despite taking one or more blood pressure lowering drugs, many people still have ‘uncontrolled’ blood pressure. Professor Morris Brown of Queen Mary University London, together with investigators all around the UK, designed the ‘Prevention and Treatment of Hypertension with Algorithm‐based Therapy’ (PATHWAY) trials to try to develop new, more personalised approaches to treating high blood pressure.

What did the studies involve?

The PATHWAY studies took place between between 2009 and 2014.

PATHWAY-1

• This study recruited 605 participants diagnosed with high blood pressure.
• It aimed to test whether high blood pressure can be better controlled when people are immediately started on a combination of blood pressure-lowering drugs.
• This was compared to starting with one drug and adding more as necessary.

PATHWAY-2

• This study recruited 335 participants with uncontrolled high blood pressure, who were already on high doses of the three recommended types of medication.
• The study aimed to find out whether a drug called spironolactone is the best add-on treatment for these patients.

PATHWAY-3

• This study explored the use of a type of diuretic which does not cause potassium to be lost from the body.
• This was important as diuretics which cause potassium loss may increase the risk of developing diabetes.
• The study recruited 441 patients who had uncontrolled blood pressure, plus other symptoms suggesting they were at higher risk of developing diabetes. For example, a slightly increased level of glucose (sugar) in their blood.

A key aspect of all of these studies was that patients were provided with home blood pressure monitors to record their own blood pressure readings. This is considered to be a better way to test how well blood pressure is being controlled, as it removes the stress of having a doctor take the measurements. Monitoring blood pressure at home also helped to reduce how often participants had to attend a clinic.

What did the studies find?

PATHWAY-1

• Initially prescribing at least two blood pressure lowering drugs can provide effective blood pressure control more quickly.
• This helps to reduce patients' time ‘at risk’.
• Importantly, people on multiple medications did not experience more side effects, such as dizziness.

PATHWAY-2

• Spironolactone was by far the most effective ‘add on’ medication for people with hard to control high blood pressure.

PATHWAY-3

• A combination of two diuretics – one which does cause potassium loss, and one that doesn't – was more effective at reducing high blood pressure compared with taking either drug alone.
• This combination also seemed to prevent any harmful effects on the control of glucose levels, suggesting it could reduce the diabetes risk associated with potassium loss.

Why are the studies important?

The results of the PATHWAY studies have fed into European and US guidelines for the management of high blood pressure. It is hoped that resulting changes in practice will help to improve the speed and efficiency of blood pressure control in people at risk of heart attacks and strokes.

Professor Morris Brown spoke to the BHF about their impact: “PATHWAY involved bringing together the UK hypertension research community under the auspices of the British Hypertension Society and attempting to identify and answer important unanswered questions. It was a huge undertaking – lots of academics got together to work on the studies but we didn’t have any support from the pharmaceutical industry or any of their infrastructure. That’s why funding by the BHF was so important for the studies.”

“Our follow-up to PATHWAY has concentrated so far on studies leading to easier diagnosis and treatment of patients whose hypertension is due to a specific cause, namely an overactive hormone gland, the adrenal gland. PATHWAY showed this condition (called primary aldosteronism) to be much commoner than previously suspected."

Study details

"A program for prevention and treatment of resistant hypertension with algorithm based therapy (PATHWAY)"
Award reference:  SP/08/002/24118
Principal Investigator: Professor Morris Brown, Queen Mary, University of London
PATHWAY-1 trial registration: NCT00994617
PATHWAY-2 trial registration: NCT02369081
PATHWAY-3 trial registration: NCT02351973

Publication details

PATHWAY-1 - Macdonald TM, Williams B, Webb DJ, et al. Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double-Blind Randomized Controlled Trial. J Am Heart Assoc. 2017;6(11)

PATHWAY-2 - Williams B, Macdonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068.

PATHWAY-3 - Brown MJ, Williams B, Morant SV, et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. Lancet Diabetes Endocrinol. 2016;4(2):136-47.