[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.
