Pharmacies are chock-full of prescription drugs to treat high blood pressure, and so are patients’ medicine cabinets. They can work well to keep blood pressure down if taken as directed, which most patients do not do.

Failure to take high blood pressure medication as prescribed is so prevalent that medical device companies, including Minnesota-run Medtronic and California’s ReCor Medical, think there’s a billion-dollar market in selling machines to treat it with a medical procedure called renal denervation.

Minnesota is a hotbed for clinical research into using devices to treat high blood pressure, in part because of strong interest from the patients, said Dr. Yale Wang, a researcher at Minneapolis Heart Institute Foundation. Wang is an investigator in several such trials, including a ReCor Medical study that began in March.

The results of these trials will be critical as proponents of renal denervation try to overcome resistance to the therapy in the medical community. The data also need to be compelling enough to sway U.S. regulators.

Meanwhile, digital health startup Geneticure in Rochester is combining artificial intelligence and DNA analysis into a service intended to tell doctors which high blood pressure drugs will work best for a particular patient.

Minnesota is also home to CVRx, a medical device maker that sells a pacemaker-like device for hypertension in Europe. The company has pivoted to testing the device for heart failure treatment in the U.S.

“Hypertension is such a problem because we don’t know what causes it, and we don’t have specific therapies that address the underlying cause,” said Dr. Sam Dudley, chief of cardiology at the University of Minnesota Medical School. “We have to continuously treat people for the outcome, which is high blood pressure.”

High blood pressure, also known as hypertension, is a risk factor for serious health problems such as stroke, heart failure and coronary heart disease. It’s been called the most important risk factor for death and disability worldwide, contributing to diseases that cause more than 9 million deaths annually and affecting more than 1 billion people, including 1 in 3 U.S. adults.

Doctors say that having a poor diet, being obese and sedentary, and smoking contribute to the disease, but genetics, age and ethnicity also play major roles.

The most conservative treatments for high blood pressure include losing weight, getting more exercise, and reducing salt and alcohol intake. Such recommendations may or may not come with a prescription for pills such as diuretics, beta blockers or vasodilators.

There are more than 60 hypertension drugs on the market, but people tend not to take them as directed, especially when they have to take pills multiple times per day. In 2017, researchers in the Netherlands reported drug testing of hypertension patients showed that 80% of them didn’t take their pills as prescribed.

More than a decade ago, optimistic results from early studies fed hopes among manufacturers that medical devices could address this problem by treating uncontrolled hypertension with devices instead of drugs. But when better-designed clinical trials were run, with features like randomization and placebo controls, much of the early benefit disappeared.

Medtronic had invested more than $800 million in a company called Ardian in 2011 based on early studies, only to see Ardian’s Symplicity renal denervation device produce about the same reductions in blood pressure as patients in the control arm who just took pills in a 2014 study. Other major device makers, such as St. Jude Medical and Boston Scientific, halted similar programs at the time.

Meanwhile, CVRx encountered problems in its clinical trials of its pacemaker-like device for hypertension, including missteps in designing the trial and problems with the device design.

CVRx’s Barostim device was redesigned, and CVRx is now focused on getting the system approved in the U.S. for heart failure, and new clinical data are slated to published Thursday.

“A lot of doctors believe they can treat any hypertension with a different cocktail of drugs,” said CVRx Chief Financial Officer John Brintnall. “And so trying to get that generation of doctors to think about using a device has been challenging.”

Indeed, patient self-referrals have been common in the ongoing clinical trials of renal denervation at Minneapolis Heart Institute Foundation, which is the site of four different ongoing clinical trials that are actively recruiting patients, including two for Medtronic and two more for ReCor.

Since the kidney is a key site for signals that drive hypertension, engineers have designed thin devices that can be temporarily inserted into the arteries leading to the kidney to disable the nerves in the vessel wall. Medtronic’s Symplicity Spyral renal denervation system uses radio-frequency energy, while ReCor’s uses ultrasound energy.

Wang, who is involved with both companies’ studies, said “it’s a consumer’s world out there” and many patients are tired of the side effects and complexities of their drug regimens.

“That kind of surprised us,” Wang said. “If you said, ‘You could do this with a pill or a procedure,’ you’d think most people would say, ‘Let’s go with the pill.’ But to our surprise, that wasn’t actually the case.”

Industry is also starting to accept the notion that technological interventions like renal denervation are going to be used in combination with drugs, rather than as an alternative, to achieve a cumulative effect.

“It’s probably safe to say that we believe that [the Ardian device] will be some type of complementary approach to the management of hypertension,” said Jason Fontana, who leads Medtronic’s global renal denervation portfolio. “That said, I think there are patients who have response enough that they may reduce or eliminate medications.”

Geneticure, the Rochester startup, is devoted to keeping patients on their drugs.

After scouring the medical literature, the company produced an initial list of 17 common genes that can predict whether certain hypertension pills will be effective or not.

“We don’t just give one recommendation, we give four recommendations, ranked based on the patient genetics,” company co-founder and Chief Operating Officer Eric Snyder said. “We really think this decision has to be made by the doctor, based on everything that is going on.”

In April, the company revealed data at an industry conference in Florida showing that in an analysis of 384 nonsmokers with family histories of hypertension, patients who took drugs recommended retrospectively by the system had 36 % lower systolic blood pressure readings compared to patients whose prescriptions didn’t match the company’s analysis.

The $249 service is available today via Geneticure’s website, though the company has plans for a large FDA-regulated clinical trial in the future.

Combining device treatments like renal denervation with pharmacogenetic insights could be a promising approach, Wang noted.

“As there is no single physiologic cause for hypertension ... complementary medications and device therapies must be considered,” Wang said. “At the end of the day, I believe all treatments will be complementary for the better care of our patients.”