When it comes to treating high blood pressure, many people are terrible at taking their pills.

That’s one big reason why cardiologists are interested in an interventional procedure called renal denervation, which offers the promise of lowering a person’s blood pressure more reliably than just taking prescription drugs alone.

Minnesota-run Medtronic is running multiple studies on it, and other major device makers like Boston Scientific and Abbott Labs have their own device designs and are watching the field closely. Hundreds of millions of dollars in future revenue could be at stake to treat tens of thousands of patients a year.

“We think the science behind this is very sound, and the need is strong,” said Sean Salmon, president of the Medtronic division that includes renal denervation therapies.

Unfortunately for device companies, though, patients’ inability to stick to their complicated daily drug regimens is also a major complication in the long-running quest to prove that the interventional procedure is effective in the United States.

Medtronic stunned the cardiology world in 2014 when its major renal denervation study, known as HTN-3, concluded that the interventional procedure worked no better than a fake placebo. Researchers later said patients’ nonadherance to drug prescriptions after the procedure likely skewed the results, among other factors.

The HTN-3 news landed like a bomb. A field once teeming with companies developing minimally invasive renal denervation machines for the U.S. quickly collapsed to just two: Medtronic and a small Palo Alto, Calif., company called ReCor Medical.

Both companies are now working on long-term clinical studies to show renal denervation can effectively lower a person’s blood pressure, regardless of whether they are taking pills for it. But to find success, they will have to come to terms with the thorny problem that a majority of patients do not take their blood-pressure drugs as directed — and they may not be truthful about it when asked.

Medtronic reported last month that 40 percent of the 80 patients in one of its most recent studies didn’t take their high blood-pressure pills as prescribed — after being informed that drug testing would be used to monitor their adherence during the trial.

“If the patient has a systolic blood pressure of 175 or 180, and they’re on four or five drugs, they’re miserable … They’re constantly going back to the doctor to minimize side effects,” said Joe Galatowitsch, a Minneapolis-based consultant with Navigant who has studied the renal denervation market. “Hypertension is not symptomatic, which is half the problem. If you stop taking the drugs, you feel better, even though maybe your systolic blood pressure went from 180 to 220.”

High blood pressure, also known as hypertension, is one of the world’s biggest public health problems.

When a person’s blood pushes too hard against their blood vessels over a long period of time, it can lead to serious problems like heart disease, heart failure and stroke. The World Health Organization attributes about 7.5 million deaths per year worldwide to blood pressure that is too high.

Besides making personal changes like reducing salt and alcohol, prescription drugs are the most common way to treat high blood pressure. A plethora of different anti-hypertension drugs is available in the U.S.

Patients whose blood pressure doesn’t drop after being prescribed a regimen of several drugs are considered to have uncontrolled hypertension.

“It’s not that these blood-pressure medications don’t work — it’s that patients don’t take them,” said Andrew Weiss, chief executive of ReCor Medical and a former Medtronic employee. “We are all looking for a treatment for high blood pressure that is safe and effective, but that also reduces dependence on [prescription] adherence.”

A device company that could effectively treat patients for uncontrolled hypertension could quickly reap revenue in the hundreds of millions of dollars a year, depending on the eligibility criteria for the procedure, according to industry analysts like Sean Messenger of Decision Resources Group in Toronto.

Renal denervation is a minimally invasive procedure in which a doctor physically severs the nerves in the arteries that lead to the kidneys.

The Medtronic and ReCor devices use different forms of energy to accomplish this painless ablation of nerves, but both rely on the principle that the kidneys are a major source of the neural signals that trigger hypertension. Strategically breaking those nerves should decrease the volume of signals that cause a person’s body to chronically enter a “fight or flight” response, which is what drives hypertension.

The renal-denervation devices being tested are narrow enough to be inserted into a blood vessel and advanced through the artery leading to a kidney. Once in place, the Medtronic device emits radio-frequency energy and the ReCor device gives off ultrasound waves that sever the nerves embedded in the arterial wall.

Such devices are already legal in other places, including some European countries. Securing approval from the U.S. Food and Drug Administration, though, will require large-scale studies showing that such systems are safe and effective as defined under U.S. law.

In the past year, Medtronic announced the results of two early proof-of-concept trials looking at its redesigned Symplicity Spyral renal denervation device. (The device was redesigned into a spiral shape and the procedure was refined after the failed study in 2014.)

For patients who went off their drugs for the recent Medtronic trial, renal denervation reduced their ambulatory systolic blood pressure by 5.5 points after six months, vs. just a half-point drop in the placebo group. (A point is one mm Hg, or millimeter of mercury. “Systolic” pressure is the upper figure in a blood pressure reading.) That “off-med” trial since has been expanded into a larger, pivotal-phase trial that will encompass hundreds of patients.

Meanwhile, for patients who remained on their drugs, the Medtronic Spyral procedure lowered ambulatory systolic pressure by 9 points at six months, vs. 1.6 points in the control group. A Medtronic spokesman said the company is still evaluating next steps for that study. Both studies included just 80 patients, and neither reported any major device-related adverse events.

ReCor also announced clinical results last month. It said that, two months after patients were taken off their medications and treated with the ReCor device, they showed an average 8.5-point drop in ambulatory systolic blood pressure, compared to a 2-point drop in a placebo arm, with no major adverse events among the 146 patients. Like Medtronic, ReCor is running multiple studies of its renal denervation device simultaneously on differing patient groups.

The magnitude of the declines in recent studies don’t impress everyone. Navigant’s Galatowitsch said a 5-point reduction in systolic blood pressure “doesn’t feel that earth-shattering to me,” especially given that most patients would likely continue taking some drugs even after renal denervation.

But Atlanta cardiologist Dr. David Kandzari, a principal investigator on the Medtronic studies and a paid speaker for the company, argued that such reductions in ambulatory systolic blood pressure are clinically significant.

He cited a 2016 analysis of past studies sponsored by the U.K.’s National Institute for Health Research that concluded a 10-point reduction in systolic blood pressure was associated with a 13 percent reduction in death from any cause, and at least a 20 percent reduction in major cardiovascular events.

ReCor’s Weiss said the process of generating the data to finally clarify the true effectiveness of renal denervation is long and complex — which he views as appropriate, given his belief that many millions of people will one day get the treatment.

Medtronic declined to comment on its renal denervation spending. ReCor is steadily raising funds to support its work, including through a development and commercialization agreement with Japanese pharma and health care supplier Otsuka Holdings Co.

“Renal denervation really works. The question is, in whom, and with what technologies, and how to do it in a way that makes sense? And after that, which patients should be treated, and under what scenarios, and what are the health economics?” Weiss said. “I’m going to have raised probably $100 million to answer those questions with our technology, and I’m sure that Medtronic is going to spend a similar amount of money to investigate theirs.”