Abstract:

[Editor's note] Primary medical institutions are the main battlefield for the prevention and control of hypertension in our country. Single-pill Combination (SPC) antihypertensive drugs are one of the main treatment drugs for hypertension, and are recommended by the guidelines for hypertension in various countries in the treatment process. At present, the application of SPC in hypertensive patients in China has been more and more extensive, and it has become an important approach to increase the rate of the compliance of hypertension. However, there are still confusions on the grasp and use of SPC in primary level. In order to enable workers in primary medical institutions to understand and manage SPC better, and to promote its standardized application in primary level, the expert group of "Regulated Hypertension Management Project for Primary Medical Institutions" in the Hypertension Professional Committee of the China International Exchange and Promote Association for Medical and Health Care formulated the "Expert Advice on the Clinical Application of Single-pill Combination Antihypertensive Drugs in Primary Medical Institutions". This recommendation is based on the characteristics of hypertension patients mainly in primary level, combining with the blood pressure advantages of SPC in our country, including: high blood pressure reduction effectiveness, clear evidence of organ protection, good medication compliance, low treatment cost and strong accessibility in primary level, put forward the expert advice on the clinical application of SPC in primary medical institutions, helping primary medical workers to use SPC better and more rationally, to manage blood pressure better and improve the blood pressure compliance rate of hypertension patients.

Expert Advice on the Clinical Application of Single-pill Combination Antihypertensive Drugs in Primary Medical Institutions   Expert Group of Standardized Hypertension Medication Management Project in Primary Medical Institutions， Hypertension Professional Committee，China International Exchage and Promotion Association for Medical and Healthcare

* Corresponding author：CHEN Yuanyuan，Chief physician；E-mail：yuanyuandao@sina.com

【Abstract】 The application of single pill combination （SPC） antihypertensive drugs has become one of the important means to improve the rate of blood pressure targeting.The control rate of hypertension in primary level is low，and primary medical institutions are the main battlefield of hypertension prevention and control in China.In order to make primary medical

workers better understand and use SPC，and to promote its standardized application in the primary level，experts in the field of cardiovascular hypertension based on the current situation of hypertensive patients mainly distributed in the primary level in China，combined with the good antihypertensive effectiveness，organ protection，medication compliance，primary accessibility and other characteristics of SPC，put forward expert suggestions on the clinical application of SPC at the primary level.The purpose is to make doctors in primary medical institutions reasonably apply SPC and help to improve the rate of blood pressure targeting in hypertensive patients.

【Key words】 Hypertension；Single-pill combination；Antihypertensive drugs；Primary medical institutions；Expert advice

In recent years, more and more single-pill combination (SPC) antihypertensive drugs with "strengthening, simplifying and optimizing" characteristic have come out one after another, which has become one of the main treatment drugs for hypertension and are widely used in hypertensive patients in China. Primary medical institutions have become the main battlefield of the prevention and control of hypertension in our country [1-2], and the more standardized blood pressure management is needed, however, due to the characteristics of blood pressure prevention and control in primary level and the work particularity of general practitioners, they are different from the grade-level hospitals, and the understanding and application of SPC may also be different. In order to enable primary medical workers to better understand and master SPC, and to promote the standardized application of SPC in primary medical institutions, domestic experts formulated the recommendation thorough discussion based on the available evidence.

1. The primary medical institutions are the main battlefield for the prevention and treatment of hypertension in our country.

A survey including 451 755 patients≥18 years old from 262 cities and rural areas in 31 provinces in our country showed that the crude prevalence rate of hypertension was 27.9%, and the awareness rate and treatment rate were 46.9% and 40.7% respectively[3]. Other studies have also suggested that 90.0% of hypertension patients in our country are located in the primary medical institutions [1]. Therefore, the primary medical institutions are the main battlefield for the prevention and treatment of hypertension in our country.

The rate of consultation in primary medical institutions for patients with hypertension in our country is relatively higher. The survey including 1 536 patients with hypertension in urban and rural areas in our country shows that 58.2% to 68.9% of the hypertension patients choose primary medical institutions[4]. Another study investigates 1,597 patients with hypertension and found that 66.4% of them choose primary medical institutions[5]. Among the elderly patients treated in primary medical institutions, hypertension is also the chronic disease which is most frequently treated (accounting for65.7%)[6]. In recent years, the National Health Commission (Health Commission) has promulgated the "Strategies for the Classification of Hypertension Diagnosis and Treatment" and proposed the treatment of hypertension should sink to the grassroots. Therefore, guiding doctors in primary medical institutions to better manage blood pressure to improve the blood pressure compliance rate of hypertensive patients has become the main task at present.

2. Hypertension control status and current status of combined therapy or SPC use in primary medical institutions

In 2012, the rate of hypertension control for adults over 18 in our country was only13.8% [7]. Some studies conducted on the hypertension patients in community showed that the control rate of hypertension was only 3.1%~5.1% [8-9]. The results of the China Hypertension Survey conducted during 2012-2015showed that amongthe entire population (451755 cases), the hypertension control rate and treatment control rate were 15.3% and 37.5%respectively, while the rural population (231,703 cases) hypertension control rate and treatment control rate were 13.1% and 34.4%respectively[3], suggestingthat the hypertension control rate of primary rural populationis lower than the entire population. It is showed that the primary hypertension control should be improved.

In primary medical institutions, the combination of antihypertensive drugs in the early years was mostly the combination of traditional antihypertensive drugs (traditional SPC). The highest proportion of dual antihypertensive drugs was diuretics + central antihypertensive drugs (61.4%). The highest proportion of triple antihypertensive drugs is vasodilator + central antihypertensive drug + diuretic (69.2%) [10]. As the novel SPC gradually integrates into clinical work, the use of SPC has become more and more widespread. The study in 2016 on the use of hypertension drugs in community of Guangdong Province showed that the use rate of SPC was 24.34% [11]. The statistical results of 250,000 primary-level hypertensive patients included in management from 2005 to 2010 showed that among the primary rural hypertensive population, 50% of them use SPC (mainly traditional SPC) [12].

3. Advantages and limitations of SPC

SPC has been clinically shown to have good antihypertensive effectiveness, organ protection, medication compliance, accessibility in primary level, it is more important that it has the characteristics of increasing the rate of compliance, should be used as one of the important treatment drugs for hypertension control in primary medical institutions.

3.1 Both traditional SPC and novel SPC can effectively reduce blood pressure.

SPC came out in the late 1950s and its main ingredients are diuretics, central antihypertensive drugs, vasodilators, sedatives in very low-dose and traditional Chinese medicines. And the current common kinds mainly include: compound reserpine and triamterene tablets (No. 0), Zhenju Jiangya tablets and compound Jiangya tablets. During 2012—2015, most of the SPC preparations used by hypertensive patients in our country were traditional SPC (92.5%) [3]. Traditional SPC has a clear antihypertensive effectadvantages including low price, few adverse reactions and good compliance [13-14]. Because of its high accessibility inprimary level, it is currently widely used in primary medical institutions, but the evidence of evidence-based medicine is relatively limited. Compound reserpine triamterene tablet is a domestically-made innovative drug independently developed by China [10], and it is the most evidence-based medicine among three traditional SPCs and widely used in primary medical institutions in China, because of its long-acting effect (1 time/d), easy to use, good effectiveness and safety, etc [15-17].

Novel SPC mainly refers to the SPC marketed in the early 1990s, including renin angiotensin inhibitor (RASI) [angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist, (ARB)] + diuretic/calcium channel blocker (CCB),CCB+β-blockers and thiazide diuretics + potassium-sparing diuretic agents[18]. The novel SPC has a clear effect on reducing blood pressure in patients with hypertension [19-28]. In patients withfailing to meet the standard of single-agent therapy, the novel SPC can quickly and effectively increase the rate of reaching the standard for restraining blood pressure [29-30]. Compared with free association, the novel SPC has a higher treatment compliance rate and earlier reaching to the standard as the initial antihypertensive drug[31-32].

3.2 SPC can protect target organs, prevent cardiovascular and cerebrovascular complications and reduce blood pressure

The benefit mainly comes from the blood pressure reduction itself [33]. Under the premise of effective blood pressure reduction, both traditional SPC and novel SPC can reduce the risk of cardiovascular events.

ACEI-based SPC can improve target organ damage and reduce the occurrence of cardiovascular and cerebrovascular events. In SPC combined with diuretics, perindopril/indapamide can reduce damage of target organs such as heart, arteries, and kidneys [22-23, 34], and can significantly reduce the risk of severe macrovascular or microvascular events, cardiovascular death and all-cause deathin patients with type 2 diabetes to 9%, 18%, and 14% respectively [35].In SPC combined with CCB, perindopril/amlodipine treatment can significantly reduce the mortality rate [36]. Another study showed that compared with hydrochlorothiazide/benazepril, primary endpoint incidentsof amlodipine/benazepril in high-risk hypertensive patients decreased by 19.6% [37].

ARB-based SPC is superior to free combination in reducing microalbuminuria in patients with hypertension and early diabetic nephropathy[38]. Studies have shown that Losartan/Hydrochlorothiazide can effectively reverse left ventricular hypertrophy (LVH) in patients with hypertension [39]. Valsartan/amlodipine can significantly reduce the risk of cardiovascular disease in patients with high-risk/severe high-risk hypertension by 43.3% [40]. Compared with free combination, the drug can also significantly reduce the risk of cardiovascular events and the risk of death, the survival rate of patients without adverse cardiovascular events increased by 17%, the incidence rate of heart failure, malignant arrhythmia and percutaneous coronary intervention (PCI) decreased, the hospitalization rate also decreased [41].

3.3 SPC has good compliance and high accessibility.

Researches have shown that, compared with low treatment compliance, patients with high treatment compliance have a 45% increase in the probability of reaching the target blood pressure, and patients with moderate and high compliance have a significant lower risk of cardiovascular events by 20% and 25% [42]. At present, the second main cause of poor blood pressure control inprimary level in our country is poor compliance (58.33%)[43]. Any type of SPC may reduce the number of medications and the number of tablets taken to a certain extent to reduce the psychological burden of patients with hypertension, which is conducive to improve compliance of patients[44]. Studies have shown that the treatment compliance of SPC is higher than that of free combination by 14.92%[45]. In addition, the occurrence of adverse reactions can affect patient compliance with medication. At present, there have been limited reports of serious adverse reactions in Chinese community patients using traditional SPC [46-47]. The novel SPC has the advantages of the additive antihypertensive effects and adverse reactions (such as hypokalemia and elevated blood uric acid, etc.) [29, 48-49]

In addition, patients with hypertension need to take medicine for a long time, and the cost of medicine is a long-term burden [50]. SPC saves medical expenses withless time to reach the blood pressure standard, fewer number of outpatient follow-up observations, effectively target organs protection and fewer cardio-cerebral vascular complications. SPChas better value/benefit and lower related medical costs compared with free combination[40,51].

3.4 Limitations of SPC use

In the treatment of hypertension patients in primary medical institutions, not all patients are suitable for SPC. For patients with cardiovascular and cerebrovascular diseases or other comorbidities, more precise drug treatment is needed. When it is necessary to increase or decrease a certain component in SPC, the fixed compound characteristics of SPC will limit the adjustment of drugs to a certain extent.

4 Expert recommendations of the SPC clinical application in primary medical institutions

In order to improve the compliance rate of primary hypertension patientsmore effectively, experts recommend early use of SPC after assessing the blood pressure and clinical risk of patients.

4.1 All kinds of traditional SPC and novel SPC are suitable for patients with hypertension in primary medical institutions. Most patients can use conventional dose SPC, and the elderly (≥ 80 years) and weak hypertensive patients should use lower doseSPC at the initial stage [52-53].

4.2 The treatment path of SPC antihypertensive drugs used in primary medical institutions has been shown in Figure 1. The common use of SPC antihypertensive drugs commonly has been shown in Table 1.

4.3Other precautions for using SPC

4.3.1 Traditional SPC (1) It is necessary to understand the components and the main adverse reactions and contraindications of traditional SPC to avoid unreasonable combination medication.(2) Traditional SPC should not be combined. Most of its main components are same or similar, although combined application may increase the antihypertensive effect, its adverse reactions may also be superimposed, leading to theincreasingly concurrence of the related adverse reactions risk.

4.3.2 Novel SPC  (1) The serum potassium, creatinine of patients need more cautious monitoring when the novel SPC containing ACEI/ARB is applied, and it also should be used with caution in patients with more moderate or impairment renal function. When applying a novel SPC containing diuretics, attention should be paid to the monitoring of electrolytes, uric acid, blood sugar and blood lipids of the patients, and it should be used with caution in patients with severe liver and kidney damage  (2) Novel SPC containing diuretics should be used with caution for gout; novel SPC containing ACEI/ARB is forbidden in patients with pregnancy, bilateral renal artery stenosis, and hyperkalemia.

5Summary

As a comm antihypertensive drug, SPC has the advantages including convenience to use, safety and effectiveness, good compliance, high compliance rate, and it conforms the principles about the selection of hypertension treatment drugs in primary medical institutions of our country. This expert advice explains the importance of SPC in primary application, antihypertensive efficacy, organ protection, etc, and provides the process of clinical use SPC in primary medical institutions. It is hoped that the hypertension patients can be better managed and the risk of cardiovascular and cerebrovascular events for high-level hypertension patients can be reduced through standardized using of SPC in primary medical institutions in China.

Key words: Hypertension, Single-pill combination, Antihypertensive drugs, Primary medical institutions, Expert advice

摘要： 单片复方制剂（SPC）降压药物的应用，目前已经成为提高血压达标率的重要手段之一。基层高血压的控制率低，而基层医疗机构又是我国高血压防控的主战场，为了使基层医务工作者更好地理解及掌握SPC、推动其在基层的规范应用，心血管高血压领域专家基于我国高血压患者主要分布在基层的现状，结合SPC良好的降压有效性、器官保护性、服药依从性、基层可及性等特点，提出SPC基层临床应用的专家建议，其目的是使基层医生合理应用SPC、有助于提升高血压患者的血压达标率。

关键词: 高血压, 单片复方制剂, 降压药物, 基层医疗机构, 专家建议