Hypertension burden growing despite available treatments; new solutions in development
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The global burden of hypertension remains high and continues to increase, despite evidence-based therapies that have been in cardiologists’ armamentaria for many years. As a result, new treatment options are being developed and clinicians are contemplating changes to management of patients who have hypertension or are at risk for it.
WHO estimates there are 1.13 billion people worldwide who have hypertension, with approximately two-thirds living in low- and middle-income countries. In 2015, 25% of men and 20% of women had hypertension. According to WHO, less than 20% of people with hypertension have it under control.
Global trends of BP show an interesting picture. The NCD Risk Factor Collaboration published data in The Lancet in 2016 from a pooled analysis of 19 million adults from 1,479 studies. In this analysis, mean systolic and diastolic BP declined in high-income Western and Asia Pacific countries from 1975 to 2015, but rose in lower-income areas including Southeast and East Asia, Oceania, South Asia and sub-Saharan Africa. The number of adults with hypertension nearly doubled during those years, with large increases in low- and middle-income countries (Graphic).
“Between 1990 and 2015 ... we have had more and different classes of antihypertensive drugs developed,” Cardiology Today Editorial Board Member George L. Bakris, MD, professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine, said in an interview. “We have had improvements in the sophistication of single-pill combination therapy. Drugs have become cheaper than they previously were for blood pressure. With all that, things have gotten worse in terms of the prevalence of hypertension.”
Determining the global prevalence of hypertension and strategies to combat increased rates may be difficult based on varying needs of different countries.
“Every country is so different in terms of the awareness level of the general public,” Cardiology Today Editorial Board Member Laxmi Mehta, MD, noninvasive cardiologist, professor in the division of cardiovascular medicine, director of the lipid clinics and section director of preventive cardiology and women’s cardiovascular health at The Ohio State University Wexner Medical Center in Columbus, said in an interview. “If there are other pressing priorities in terms of medical issues, those take precedence sometimes. The concept of preventative care may vary in different countries. Access to care is a big issue as well. Access to medications, access to health care visits and access to home blood pressure monitoring devices can sometimes be a conflict with other pressing priorities such as access to food, water and shelter. This makes it a challenge.”
Persistent increase in prevalence
Several factors may underlie the global increase in hypertension rates.
“The primary cause of elevated blood pressure in most patients is termed primary hypertension, previously called essential hypertension,” Cardiology Today Editorial Board Member Keith C. Ferdinand, MD, FACC, FAHA, Gerald S. Berenson Endowed Chair in Preventive Cardiology and professor of medicine at Tulane University School of Medicine in New Orleans, said in an interview. “It is a mixture of environmental stressors, high sodium/low potassium diet, increasing obesity, stress, urbanization, responses to pollution and a general increase in the dietary and environmental factors that lead to high blood pressure. Only a minority of these patients are related to secondary causes, things which are easily identifiable and corrected.”
Hypertension is also increasing due to aging populations, sedentary lifestyles, obesity and urbanization.
“We are more industrialized around the world,” Wanpen Vongpatanasin, MD, director of the hypertension fellowship program, professor in the department of internal medicine, Norman and Audrey Kaplan Chair in Hypertension and Fredric L. Coe Professorship in Nephrolithiasis Research in Mineral Metabolism at University of Texas Southwestern Medical Center, told Cardiology Today. “We have become more cognizant of the unhealthy lifestyle around the world, including obesity, physical inactivity and consumption of unhealthy food and high salt from processed food. That all contributes to high blood pressure. Furthermore, people live longer and hypertension prevalence increases with age.”
Although medications are available to manage hypertension, adherence is exceedingly poor, experts told CardiologyToday. Even with affordable medications, patients may be prone not to take the treatment because hypertension is an asymptomatic disease, Bakris said.
Beyond these risk factors, another factor may be the revised definition of hypertension according to the American Heart Association/American College of Cardiology guideline released in 2017, which defined hypertension as BP at least 130/80 mm Hg.
“When you lower the definition of such a prevalent disease, then obviously there will be a lot of patients who now fall into the definition and are hypertensive even if they were perfectly normotensive before,” Cardiology Today Editorial Board Member Franz H. Messerli, MD, FACC, FESC, professor of medicine at the Swiss Cardiovascular Center at the University of Bern and at Icahn School of Medicine at Mount Sinai, said in an interview.
Given what is known about potential causes for increasing global rates of hypertension, the trend may continue to get worse before it gets better, Paul K. Whelton, MD, MSc, professor and Show Chwan Health System Endowed Chair in Global Public Health at Tulane University School of Public Health and Tropical Medicine, told Cardiology Today. “Our epidemic of atherosclerosis is a manifestation of culture, and until a culture changes, we are not going to get rid of it with drugs and surgery,” he said. “That is a useful component of managing illness and trying to prevent illness, but it will not get rid of the problem.”
Efforts to reduce burden
Cardiologists are generally aware of how to combat and treat hypertension with strategies including lifestyle modifications and effective pharmacotherapy when needed, experts told Cardiology Today. Patients who are nonadherent to medications and/or who have resistant hypertension may benefit from the addition of a mineralocorticoid receptor antagonist like eplerenone or spironolactone if they are taking three or more medications including long-acting calcium channel blockers, renin-angiotensin-aldosterone system inhibitors and diuretics.
Whether or not a cardiologist is included in the care plan, there is a need for collaboration with other health care professionals, including primary care physicians and nephrologists, among others.
“As cardiologists, we need to partner across the aisles of the house of medicine on treating hypertension,” Mehta said. “I do not think every hypertensive patient needs to see a cardiologist. Cardiologists and cardiovascular team members need to be in the forefront — in terms of the awareness campaigns, optimization of medication regimens and hypertension research along with partnering our colleagues in primary care, nephrology and gynecology.”
Messerli said cardiologists typically focus on events that occur as a result of hypertension rather than the prevention of the condition itself.
“When you look at hypertension in general, it is more an issue of the primary care physician than it is of the cardiologist,” he said. “The cardiologist is more interested in coronaries, valves, arrhythmias and, most of all, interventional procedures. Hypertension is somewhat of an afterthought for most cardiologists. Basically, most practicing physicians have learned and are experienced in managing hypertension themselves. If a referral is deemed necessary, it may go to either nephrologist, endocrinologist or cardiologist, often depending on personal preference.”
Making an impact on the global prevalence of hypertension may extend beyond cardiologists and health care professionals to policymakers.
“This needs to be a community effort with the government, policymakers, physicians, health care professionals on all levels coming together to educate and empower people to have healthier lifestyles and, if medications are needed, to seek medications,” Bakris said.
Community-based interventions could help individualize the care needed for specific areas, as shown in several studies over the years. In a study presented at the European Society of Cardiology Congress in September 2019 and published in Nature Medicine in February, a pragmatic population-wide salt substitute strategy implemented in Peru, which consisted of 75% sodium chloride and 25% potassium chloride, contributed to reductions in systolic and diastolic BP, especially in participants who were at high risk. Other community-based interventions including those at barbershops and churches have gained attention in recent years.
Regardless of the tactics that will lead to decreases in the global prevalence of hypertension, cardiologists have the tools and skills they need to make an impact, experts told Cardiology Today.
“I am cautiously optimistic that we are going to do better,” Whelton said. “We are not going to change the world overnight, but I am optimistic that we will make some inroads.”
Lifestyle changes including diet, sleep and physical activity can contribute to BP reductions that can equal two full doses of antihypertensive medications, Bakris said, noting that, unfortunately, cardiologists often do not have the time to discuss this with their patients.
“They know what to do, and if you give them the time, they will do it,” Bakris said. “However, they have not been given the time, they are not even getting paid for the time that they are being given — not appropriately, and so at the end of the day, the patient does not get the information, the patient does not know what to ask for, they are there for advice, the physician may know, but he has 15 other people waiting and the system has deteriorated to this assembly-line mentality, which is ridiculous when a matter is very treatable but requires education.”
New device and drug treatments
Although numerous evidence-based drug and device therapies exist, new development continues.
One area of focus is renal denervation, during which renal sympathetic nerves undergo catheter-based ablation. This procedure can potentially reduce BP by enhancing renal tubular sodium excretion and decreasing renal renin release. Renal denervation with the Symplicity Spyral system (Medtronic) was shown to lower BP in the SPYRAL-HTN ON MED trial published in The Lancet in 2018. At 6 months, patients assigned renal denervation had greater reductions in office systolic BP (difference, –6.8 mm Hg; 95% CI, –12.5 to –1.1) and office diastolic BP (difference, –3.5 mm Hg; 95% CI, –7 to 0) compared with those assigned a sham procedure. Similar results were observed in the RADIANCE-HTN SOLO trial published in Circulation in 2019. In this trial, endovascular ultrasound renal denervation with the Paradise system (ReCor Medical) resulted in a mean BP reductions of 18.1 mm Hg compared with 15.6 mm Hg with sham control (difference adjusted for baseline BP and number of medications, 4.3 mm Hg; 95% CI, –7.9 to –0.6). The trials came after the failure of the SYMPLICITY HTN-3 trial in 2014, which prompted researchers and manufacturers to reconsider how to make and use the technology. These devices are not yet FDA-approved.
“It is not entirely clear at the present time how to identify the best patients whose BP will actually respond to renal denervation,” Messerli said. “In some patients, there is absolutely no response; in others, their blood pressure goes down nearly nine points and stays down for weeks and months. But we cannot predict at the present time who will and who will not be a responder.”
A novel endovascular baroreflex amplification system (Mobius HD, Vascular Dynamics) is also generating interest for hypertension. This device, used in a minimally invasive procedure to amplify the natural baroreceptor response in the carotid sinus, is currently being studied in the CALM-2 trial, which will evaluate effectiveness and safety in patients with resistant hypertension despite maximally tolerated, guideline-directed therapy.
Another area of interest is stimulating the peripheral nerve, such as the median nerve, which has been shown to inhibit the sympathetic nervous system and BP in animals and, more recently, in a small pilot study in humans published in Scientific Reports in 2018. It was thought that electrical stimulation of C-fibers in the median nerve reduces BP similar to the effects of acupuncture on BP.
“If you have an implanted device that stimulates your peripheral nerve on a regular basis, it might have more sustained effects,” Vongpatanasin said.
New drug treatments are also being studied at this time, but it remains unclear if new options will provide additional benefit beyond what is currently available.
A brain aminopeptidase A inhibitor (firibastat, Quantum Genomics) is one of several agents that may lower BP in patients with hypertension. In a study conducted by Ferdinand and colleagues, published in Circulation in 2019, firibastat lowered systolic automated office BP by 9.5 mm Hg and diastolic automated office BP by 4.2 mm Hg (P < .001), with significant reductions across all subgroups regardless of race, age, sex and BMI.
“This agent ... appears to show benefit in patients who are more difficult to treat with conventional renin-angiotensin blocking agents, and that includes patients with obesity, salt sensitivity and minority patients, especially African Americans,” Ferdinand said.
SGLT2 inhibitors may serve as a novel approach to control hypertension. Although currently approved for patients with diabetes, with some now expanded for CV risk reduction, the SGLT2 inhibitors may also confer natriuresis, modest volume depletions and changes in arterial compliance.
Other drugs in the pipeline that may have an effect on BP include finerenone (Bayer), which is in development for kidney disease, and esaxerenone (Daiichi Sankyo), both nonsteroidal mineralocorticoids.
“The advantage of [nonsteroidal mineralocorticoids] is they block aldosterone, and so they do lower blood pressure,” Bakris said. “However, the magnitude in the increase of potassium is significantly less than what you would get with spironolactone, so you do not need to worry about hyperkalemia as much as you would using the traditional spironolactone molecule. This is a class of drugs that is redeveloping.”
The concept of a polypill has also gained traction for hypertension, especially outside the U.S. A polypill strategy — combining several medications in one pill — may especially be helpful in socioeconomically vulnerable, low-income areas.
“Sure, there are medications out there that are on the horizon, but there are quite a few tried-and-true medications that are being formulated into polypills which hopefully may increase access and compliance, both of which are issues in global hypertension,” Mehta said.
Worldwide focus
Reducing the global burden of hypertension will require effort from health care professionals from different areas and policymakers to prevent not only hypertension, but also other associated conditions.
“Despite adverse lifestyle and environmental concerns, physicians, both primary care and specialists, must help the population curtail the rates of poorly controlled hypertension and resistant hypertension only by recognizing that hypertension is indeed not the silent killer, but the primary cause of increase in cardiovascular morbidity and mortality, and community-based heart failure the most predominant cause. Only by recognizing these factors will the disease itself be curtailed or controlled,” Ferdinand said.
It is also important to take into consideration where in the world patients are being treated, how their health care systems are set up and, most importantly, how to work together to achieve the greater goal of reducing the global burden of hypertension.
“Long story short, we can help one another,” Whelton said. “We can go to developing countries and see how they manage their resources very efficiently, but they do not have the same resources we have. We can help them to learn from our experience because we have gone through already many of the challenges that they’re facing right now. We are much more alike than we are different around the world.” – by Darlene Dobkowski
- References:
- Azizi M, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.040451.
- Bang SK, et al. Sci Rep. 2018;doi:10.1038/s41598-018-33402-1.
- Bernabe-Ortiz A , et al. Nat Med. 2020;doi:10.1038/s41591-020-0754-2.
- ClinicalTrials.gov. CALM-2 – Controlling and Lowering Blood Pressure With the MobiusHD. Available at: www.clinicaltrials.gov/ct2/show/NCT03179800. Accessed Feb. 19, 2020.
- Ferdinand KC, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.040070.
- Kandzari DE, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)30951-6.
- Muñoz D, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1815359.
- NCD Risk Factor Collaboration. Lancet. 2016;doi:10.1016/S0140-6736(16)31919-5.
- Roshandel G, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31791-X.
- Weber MA, et al. JACC Cardiovasc Interv. 2020;doi:10.1016/j.jcin.2019.10.061.
- Vascular Dynamics. MobiusHD System. Available at: www.vasculardynamics.com. Accessed Feb. 27, 2020.
- World Health Organization. Hypertension. Available at: www.who.int/news-room/fact-sheets/detail/hypertension. Accessed Feb. 17, 2020.
- For more information:
- George L. Bakris, MD, can be reached at gbakris@gmail.com.
- Keith C. Ferdinand, MD, FACC, FAHA, can be reached at kferdina@tulane.edu.
- Laxmi Mehta, MD, can be reached at laxmi.mehta@osumc.edu; Twitter: @drlaxmimehta.
- Franz H. Messerli, MD, FACC, FESC, can be reached at messerli.f@gmail.com.
- Wanpen Vongpatanasin, MD, can be reached at wanpen.vongpatanasin@utsouthwestern.edu; Twitter: @drwanpen.
- Paul K. Whelton, MD, MSc, can be reached at pwhelton@tulane.edu.
Disclosures: Mehta and Whelton report no relevant financial disclosures. Bakris reports he is the principal investigator of the FIDELIO trial funded by Bayer and on the steering committee for the CALM-2 trial sponsored by Vascular Dynamics and for the FLOW trial funded by Novo Nordisk. Ferdinand reports he is a consultant for Boehringer Ingelheim and Quantum Genomics. Messerli reports he is on the advisory board for Medtronic and has received financial support from Menarini, Novartis, Pfizer and Servier. Vongpatanasin reports she received funding from the American Heart Association and the NIH.
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