A Japan nationwide web‐based survey of estimation on patients for renal denervation based on blood pressure level and the number of antihypertensives (J‐NEEDs survey)

Abstract Catheter‐based renal denervation (RDN) is currently being developed as a new complementary treatment option for hypertension. RDN has not yet received approval in Japan and so the number of possible candidates for RDN in Japan also remains unknown. A total of 10 756 hypertensive patients who regularly visit medical institutions and reported their latest home blood pressure (BP) values were identified from registrants at an online research company. They filled out a survey regarding their prescribed antihypertensives and latest BP values in March 2020 in Japan. The mean age of the patients was 61.3 years old (83.5% male). According to JSH 2019, the prevalence of resistant hypertension (RHT) was estimated to be 1.4% (0.52% having an office BP of 140/90 mm Hg or more while taking three antihypertensives, including diuretics; 0.84% taking four or more antihypertensives regardless of BP level). Assuming the indication for RDN was RHT with morning home systolic BP (HSBP) ≥ 135 mm Hg and office systolic BP (OSBP) ≥ 140 mm Hg, the number of candidates for RDN was estimated to be approximately 340 000 and 372 000, respectively. When hypertensive patients prescribed three or more, two, one, and no antihypertensives were included, the estimated number based on uncontrolled HSBP and OSBP cumulatively increased 2.6, 14.2, 40.6, and 58.0‐fold; 1.8, 8.6, 25.3, and 36.4‐fold, respectively. These findings revealed that a substantial number of hypertensive patients are unable to adequately control their BP level with existing treatments, and new complemental therapies, such as RDN, would alleviate the burden of hypertension in this population.


INTRODUCTION
Management of hypertension is essential to prevent cardiovascular (CV) diseases. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH) in 2014 selected calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEi), and diuretics as the first-choice drugs for hypertensive patients without compelling indications. 1 However, according to the latest National Health and Nutrition Survey 2018, there has been no clinically significant improvement in office blood pressure (BP) over the last 10 years. 2

JSH 2019
was issued 5 years after JSH 2014 and adopted the same first-choice drugs. 3 It is necessary to understand to what extent the antihypertensives prescribed actually follow the guidelines.
Another critical point in JSH 2014 was that home BP was prioritized more than office BP. 1 Multiple clinical studies have reported that home BP has greater predictive power for CV event rates than office BP. [4][5][6][7][8] However, no research has nationally examined home BP in recent years. Therefore, it is necessary to understand the current status of home BP to determine how many patients potentially need additional treatment.
Catheter-based renal denervation (RDN) was developed to improve BP mainly among patients diagnosed with resistant hypertension.
Early clinical trials, such as SYMPLICITY HTN-1 9,10 and SYMPLICITY HTN-2 11 showed significant improvements in BP. Unfortunately, SYMPLICITY HTN-3, a subsequent comparative study with the sham group, failed to show a significant reduction in BP. 12 Subsequently, ablation techniques and devices have improved, and SPYRAL HTN-Off MED, 13,14 and RADIANCE-HTN SOLO, 15,16 double-blind comparative studies with the sham group, showed some effectiveness. Meanwhile, in a comparative study with a sham group and patients with moderate uncontrolled hypertension who were on one to three antihypertensives, early results for SPYRAL HTN-ON MED 17 showed a statistically greater improvement of BP at 6 months after RDN. In a RADIENCE-HTN TRIO 18 study in which patients with resistant hypertension were randomly assigned to a sham group and an RDN group, the RDN group also showed a significantly larger reduction in BP after 2 months.
These results suggest that RDN is a promising new option for the management of both resistant and uncontrolled hypertension, including treatment-naïve hypertensive patients.
Although some pre-market clinical trials are on-going in Japan, the

The number of prescribed antihypertensives
The number of antihypertensives per day was classified as none, one, two, and three or more, based on the class of drugs.

Home and office BP
The patients were asked to report the latest two morning home BP readings measured using their own BP monitoring device before taking antihypertensives, and the mean of morning BP was calculated for analysis. In addition, the patients were asked to report the latest office BP measured based on the method chosen by their physician's discre-

Reference studies to compare the currently prescribed drugs and BP level
Because this was a cross-sectional study, four preceding studies [20][21][22][23][24] were used to compare previous antihypertensives prescribed and BP management status (Supplementary 1). In addition, three preceding studies [25][26][27] were used to identify changes in home and office BP based on antihypertensive drug treatment (Supplementary 2).

2.5
Estimation of the number of hypertensive patients JSH 2019 estimated the total number of hypertensive patients in Japan to be 43 million. 3 It was multiplied by the frequency of each BP level or BP phenotype identified in this study to estimate the number of hypertensive patients in each group.

2.6
Statistical analyses SAS
The total number of medications including antihypertensives per day was 6.2 ± 6.1 for the two antihypertensives group and 9.0 ± 6.9 for the three or more antihypertensives group, which were significantly higher compared with the one antihypertensive group (4.8 ± 5.6 drugs) (p < .05, p < .01, respectively). CCBs and ACEi/ARB were the first and second most commonly prescribed in either group.
Diuretics were prescribed to 47.5% of patients in the three or more antihypertensives group, which is about five times greater than in the two antihypertensives group. Resistant hypertension based on JSH 2019 accounted for 1.4% of all hypertensive patients. The prevalence increased to 1.8% when a newly recommended control target of < 130/80 mm Hg is adopted according to 2017 American College of Cardiology/AHA guideline. 28 All comorbidities were more common in the resistant hypertension group than the others. In particular, diuretics were prescribed in 84.9% of the patients, Thiazide diuretic in 52.1%, MR blocker in 35.6%, and loop diuretic in 24.0% (Table 2).

DISCUSSION
This study is the latest nationwide survey to determine not only the medication status including antihypertensives but also home and office BP control in Japanese hypertensive patients.  but not provided, has been reported. 29 It also has been reported that Abbreviations: BP, Blood pressure; HBP; Home blood pressure; HSBP, Home systolic blood pressure; OBP, Office blood pressure; OSBP, Office systolic blood pressure; SBP, Systolic blood pressure. a Resistant hypertension is defined as having an office blood pressure of 140/90 mm Hg or more while taking three antihypertensive medications, including diuretics, or taking four or more antihypertensive medications regardless of blood pressure level. b BP Phenotype is classified as well-controlled (office blood pressure is < 140/90 mm Hg and home blood pressure is < 135/85 mm Hg), white coat hypertension (office blood pressure is ≥140 mm Hg and/or 90 mm Hg and home blood pressure is < 135 mm Hg/85 mm Hg), masked hypertension (office blood pressure is < 140 mm Hg/90 mm Hg and home blood pressure is ≥135 mm Hg and/or 85 mm Hg), and sustained hypertension (office blood pressure is ≥140 mm Hg and/or 90 mm Hg and home blood pressure is ≥135 mm Hg and/or 85 mm Hg). c Uncontrolled HSBP is defined based on only home systolic blood pressure of 135 mm Hg or more. d Uncontrolled OSBP is defined based on only office systolic blood pressure of 140 mm Hg or more.

Current status of home BP and its changes over 20 years
more antihypertensive prescriptions are accompanied by challenges such as poor adherence, 30 side effects, 31 and prescribing cascade that responds to the side effects of more medicine with further increases. 32 A medicine increase is known to cause problems with polypharmacy, especially when six or more drugs are prescribed, which can lead to increased side effects. 33 In this study, it should be noted that the total number of medications per day in patients prescribed two or more anti-hypertensives exceeded six drugs. Therefore, in patients taking more than two antihypertensives, increase in antihypertensives may not be always appropriate. Also, since younger adults are suggested to be one of /responders to RDN from pathophysiological view point 34

Changes in medication therapy based on the JSH guidelines
In this study, CCBs were most commonly prescribed, followed by ACEi/ARBs, confirming the continuation of trends in accordance with JSH guidelines. Diuretics were prescribed for only 7.1% of hypertensive patients taking at least one antihypertensives, despite diuretics being one of the first-line drugs. They were more frequently prescribed for resistant hypertension (84.9%) and patients with three or more antihypertensives (47.5%) compared with patients with two (9.7%) and one antihypertensives (2.4%). Although the importance of diuretics has been emphasized in updates of the Japanese Society of Hypertension Guidelines for the Management of Hypertension for the last 20 years, diuretic prescription rate in overall patients remained less than 10% both in J-HOME 20 that conducted in 2003 and in the current study. Among hypertensive patients with three or more antihypertensives, the diuretic prescription rate was 1.5 times higher in the current study (47.5%) compared to J-HOME 20 (31.6%).
Nonetheless, hypertension control did not improve at the same rate.
In addition, regardless of the fact that the MR blocker is recommended for resistant hypertension by JSH2019, this study revealed that it was prescribed for only one-third of cases of resistant hypertension. These results indicated that there is still room for improvement in adopting JSH2019.

Estimation of uncontrolled and resistant hypertensive candidate patients for RDN
This study revealed that, depending on the use of home or office BP to define uncontrolled hypertension, the number of candidates for RDN with resistant hypertension was estimated to be at least 340 000 or 372 000, respectively. The estimate increased 40.6-fold and 25.3fold when including uncontrolled hypertensive patients prescribed at least one antihypertensives. Further, when all uncontrolled hypertensive patients included, the estimate soared to 58.0-fold and 36.4-fold.
As hypertensive patients would need to be carefully screened for RDN by assessing BP control level using 24-h ambulatory BP monitoring to detect daytime and nocturnal hypertension, confirming adherence to the prescribed antihypertensives, excluding secondary hypertension, and determining the appropriateness of renal artery anatomy, a multidisciplinary approach is necessary for the appropriate application of RDN. 36 Although the actual number of hypertensive patients who eventually undergo RDN would be much less than the estimate, further consideration will be crucial in the adoption of RDN as a standard of care.
This study is highly representative of the actual situation in Japan due to a large number of cases and the fact that information was collected from all over Japan. In addition, because the most recent BP reading measured at home was submitted by the participants, it was considered highly reliable. On the other hand, there are certain limitations. The results cannot be directly applied to countries other than Japan. Since it was a self-reported internet survey, source verification was not performed and there may have been fewer responses from hypertensive patients who are unfamiliar with the internet and older adults. Another limitation was the lack of an adherence assessment and 24-h ambulatory BP monitoring which are current standard procedures for confirming eligibility for RDN in clinical studies. Moreover, the number of candidates for RDN was a crude estimate because the prevalence of hypertension by age and sex in the Japanese population was not available. Also, the number of candidates may have been overestimated by at least 12.2% because secondary hypertension 37,38 was not distinguished or excluded.

CONCLUSIONS
In conclusions, when the indications for RDN were limited to resistant hypertension with uncontrolled home and office BP, it was estimated that the number of candidates for RDN would be at least 340 000 and 372 000, respectively. The number of candidates might increase more than twenty-five-fold when RDN is used to treat patients with at least one antihypertensive and more than thirty-six-fold when RDN is used to treat all uncontrolled hypertensive patients. Side effects induced by the dose escalation of antihypertensives was a concern because one-third of hypertensive patients have already been prescribed six or more medications in total. Therefore, complementary treatment options, such as RDN, are needed for substantial hypertensive patients to improve hypertension control. More research is necessary to comprehensively quantify hypertensive patients who require complementary treatment.

FUNDING
This study was financially supported by Terumo Corporation.