Abstract
There is currently few research on clinical characteristics and outcomes of coronary heart disease (CHD) with resistant hypertension in central region of China. This study aimed to assess the risk factors and outcomes of CHD and resistant hypertension in population of central region of China. A total of 1467 CHD patients with hypertension were included and considered to three groups according to blood pressure control: controlled group (blood pressure < 140/90 mmHg on three or less antihypertensive drugs); uncontrolled group (blood pressure ≥ 140/90 mmHg on two or less antihypertensive drugs); or resistant group (blood pressure ≥ 140/90 mmHg on three antihypertensive drugs or < 140/90 mmHg on at least four antihypertensive drugs including diuretic). The authors evaluated the clinical outcomes of three groups at 1‐year follow‐up. The prevalence of resistant hypertension was 21.8%. Significant adjusted associated factors of resistant hypertension included per unit changes body mass index (BMI, OR 1.12), and four categorical variable diagnosis by yes or no: heart failure (HF, OR 2.62), left ventricular hypertrophy (LVH, OR 2.83), diabetes (OR 1.55), and chronic kidney disease (CKD, OR 1.63). In multiple adjusted Cox regression analysis, patients in resistant group had a higher risk of the primary outcome (HR, 2.14 [95% CI, 1.47–3.11]; p < .001). Moreover, the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with resistant hypertension is also significantly increased (HR, 2.11 [95% CI, 1.39–3.20]; p < .001). In conclusion, resistant hypertension was a quite common and high proportion finding in patients with CHD and hypertension in central region of China, and these patients have a worse clinical prognosis.
Keywords: coronary heart disease, hypertension, outcome, resistant hypertension
1. INTRODUCTION
The World Health Organization (WHO) states in 2021 that high blood pressure has become the leading risk factor for death and disability worldwide. 1 Despite regional differences, absolute blood pressure levels in Asia are currently the highest in the world, and blood pressure control rates are relatively low. Hypertension is a widespread and burdensome disease throughout Asia. 2 , 3 , 4
Resistant hypertension is defined as blood pressure that does not remain within the normal range despite the administration of three antihypertensive medications at maximally tolerated doses, including a diuretic, or blood pressure that can be effectively controlled by taking four or more antihypertensive drugs. 5 Although the definition is clear, there is still no precise estimate of the prevalence of resistant hypertension worldwide. Some observational studies and clinical trials estimate the incidence of resistant hypertension is 12%–49%. 6 , 7 Hypertension is one of the most important risk factors for cardiovascular morbidity and mortality, especially stroke, ischemic heart disease, chronic kidney disease (CKD), congestive HF, aortic aneurysm, and peripheral arterial disease (PAD). 8 , 9 , 10 Compared with the controlled hypertension, the risk of resistant hypertension in all‐cause mortality, cardiovascular mortality, and non‐fatal stroke increased significantly. 11 , 12
The results of the REACH trial show that in patients with the entire atherosclerotic disease spectrum, whether it is currently asymptomatic, in the subclinical or has been identified in patients with single or multiple vascular disease, resistant hypertension caused varying degrees of adverse results. 8 Although the REACH study included 709 people in mainland China, the results did not significantly represent the characteristics of resistant hypertension in China considering the influence of confounding factors such as age, ethnic, and geographical distribution. 8 , 13 According to China PEACE Million Persons Project, the central region of China has the highest awareness, treatment, and control rate of hypertension. 14 However, the exact prevalence of resistant hypertension in patients with coronary heart disease (CHD) in central region of China is unknown currently. Moreover, for population of central region of China who have developed atherosclerotic CHD, whether it also has more serious consequences if they are combined with resistant hypertension has not been studied. We sought to fill this gap in knowledge and further describe the associated factors of CHD with resistant hypertension, clinical manifestations, and cardiovascular prognosis, so we designed this prospective, observational study enrolled inpatient with prior history or newly diagnosed CHD patients.
2. METHODS
2.1. Study design and participants
This clinical trial is a single‐center, prospective observational, hospital‐based study approved by the ethics committee of Zhengzhou University Central China Fuwai Hospital (No. 2021‐20). Before being enrolled, all patients complete an informed consent form. Patients with CHD and hypertension who were between the ages of 18 and 75 were enrolled from Zhengzhou University Central China Fuwai Hospital in accordance with the trial procedure. Patients diagnosed with secondary hypertension, pregnancy, history of acute stroke, pulmonary embolism and large vessel embolism within 3 months, severe mental disorders, combined with severe respiratory failure, HF, malignant tumor disease, liver and kidney disease, and other life expectancy less than 1 year were excluded.
2.2. Clinical outcomes
The primary endpoint of this clinical trial was a compound endpoint, defined as the first occurrence of all‐cause mortality or total nonfatal cardiovascular disease (CVD) events within 1‐year follow up. The total CVD was defined as follows: (1) Nonfatal stroke/transient ischemic attack (TIA), defined as the sudden onset of a neurological deficit persisting for ≥24 h in the absence of any other disease that could account for the symptoms, with the findings of brain computed tomography or magnetic resonance imaging; (2) Nonfatal CHD, defined as acute myocardial infarction (MI), unstable angina requiring coronary revascularization [percutaneous coronary intervention (PCI) OR coronary artery bypass grafting (CABG)]; and (3) HF, defined as requiring hospitalization and treatment due to clinical manifestations of HF. 11 , 15 Among them, stroke/TIA and CHD events were classified ASCVD events. Secondary endpoint included individual components of the primary endpoint. When there was more than one endpoint event occurred during the follow‐up period, the first event data were statistically analyzed. The endpoint events were independently categorized by three cardiovascular specialists who were not aware of the baseline information. When there were disagreements regarding event identification, the three experts came to a decision together after talking.
2.3. Follow‐up and assessments
Following enrollment, baseline data on each patient were collected, including their age, sex, height, weight, baseline blood pressure, detailed drug use (administration time and dose), personal and family medical history, as well as the results of their cardiac ultrasound and the blood lipid, blood glucose, and clinical laboratory tests. Clinical follow‐up was carried out by skilled clinicians in outpatient or telephone contact at the time points of 1, 6, and 12 months, and standard computerized case report forms were filled out at each of these intervals. The occurrence of the primary and secondary endpoint events, changes in the history of drug treatment throughout the follow‐up period and details of current medications, height and weight for calculating BMI value, office or home blood pressure and heart rate were the key follow‐up indicators.
2.4. Monitoring of blood pressure
The measurement of blood pressure during admission was mainly based on the 2017 ACC/AHA guidelines. 16 The measurement of blood pressure in the inpatient department of our hospital uses the Omron oscillometric blood pressure device. The main measurement points include the following: Before the measurement, inform the patient: (1) Avoid caffeine, exercise, and smoking for at least 30 min; (2) Emptying the bladder; and (3)Relax and sit in a chair for at least 5 min (feet on the floor, back supported). Measurement: (1) Place the middle of the cuff at the right atrial level of the patient's upper arm (the midpoint of the sternum); (2) During the rest period or measurement period, patients and observers should not gossip; (3) During the first measurement, the blood pressure of both arms was recorded, and the arm with higher blood pressure reading was used in the subsequent reading; three blood pressure measurements should be interval of 1–2 min. The first blood pressure reading was discarded, and the average of the second and third blood pressure readings was taken as the final analysis value.
2.5. Definitions
CHD is defined as having at least one of the following conditions: percutaneous coronary angiography or computed tomography angiography (CTA) examination showed that at least one coronary artery trunk or primary branch had ≥50% stenosis; or typical exertional angina symptoms with positive stress test (electrocardiogram stress test, stress echocardiography, or nuclide myocardial stress imaging); or previously diagnosed MI; or previously diagnosed unstable angina pectoris (typical ischemic chest pain + ECG changes + increased markers of muscle damage; or the dynamic changes of ST segment during ischemic attack, or coronary angiography confirmed the existence of severe lesions leading to symptoms). 17
Initial diagnosis of hypertension or a history of hypertension that is currently being treated with an antihypertensive medication are included in the definition of hypertension. The most recent WHO hypertension guidelines were used to define the initial diagnosis of hypertension. 1 Patients were classified as having hypertension if their systolic blood pressure (SBP) was greater than 140 mmHg or their diastolic blood pressure (DBP) was no less than 90 mmHg. To investigate the effects of resistant hypertension, all patients were considered to three groups based on their use of antihypertensive medication and blood pressure control during hospitalization, and the average blood pressure measurement on the day of discharge was finally identified as the baseline blood pressure of the patient. The specific grouping criteria are: controlled group is defined as blood pressure <140/90 mmHg while taking three or fewer antihypertensive drugs; uncontrolled group is defined as blood pressure ≥ 140/90 mmHg while taking two or fewer antihypertensive drugs; and finally, resistant group is defined as blood pressure ≥ 140/90 mmHg on three antihypertensive drugs or <140/90 mmHg on at least four antihypertensive drugs including diuretic.
BMI is calculated by dividing weight (kg) by the square of height (m). Smoking is divided into never/ever/current smoking; drinking is divided into never/ever/current drinking. The estimated glomerular filtration rate (eGFR) was calculated using the 2009 creatinine equation of the Chronic Kidney Disease Epidemiology Association 18 ; CKD was defined as eGFR < 60 mL/min/1.73 m2 on the basis of The KDIGO CKD Clinical Guideline. 19 LVH was defined as the sum of voltage amplitudes of SV1 and RV5 was equal to or greater than 3.5 mV on electrocardiogram according to the Sokolow–Lyon criterion. 20
2.6. Statistical analysis
Continuous data that meet the normality test are expressed as mean ± standard deviation (SD), and categorical variables are expressed as percentages (%). The continuous variables included age, BMI, total cholesterol (TC), low‐density lipoprotein (LDL) cholesterol, eGFR; categorical variables included sex, smoking, drinking, history of diseases, and usage of medications. One‐way analysis of variance (for continuous data) or Fisher's exact test or χ2 test (for categorical data) was used to compare the demographic variables and clinical characteristics of three groups, and the results were Bonferroni's corrected (for multiple comparisons). We used stepwise logistic regression to identify variables that were highly correlated or predictive of resistant hypertension, with p < .1 as the cut‐off point into the model and p < .05 retained in the final model. The cumulative incidence of endpoint events in the three groups were analyzed using the Kaplan–Meier curve; Cox proportional hazards model was used to calculate the hazard ratio (HR) and 95% CI of endpoint events. Cox Model 1 was unadjusted model. Model 2 was adjusted by confounding factors including age, sex, BMI, smoking, diabetes. Model 3 was further adjusted for TC, LDL cholesterol, eGFR, statin use, established CVDs including MI, stroke/TIA, and HF, and revascularization therapy (ever and during this hospitalization). All statistical analyses were performed using SPSS software. 27.0 (Spss Inc.) and p < .05 was defined as statistically significant.
3. RESULTS
3.1. Study population
Overall, our study is a single‐center, prospective, observational, hospital‐based clinical study. From January 2021 to December 2021, a total of 1778 patients who had CHD and hypertension were recruited in the study, of which 185 patients were excluded according to the following exclusion criteria: lack of detailed laboratory data, death during hospitalization due to acute MI, end‐stage HF, severe liver or renal diseases or malignancy with a life expectancy of less than 1 year; 47 patients with secondary hypertension were excluded, and 79 patients were lost to follow‐up during the 1‐year follow‐up period after discharge. Therefore, a total of 311 patients were excluded, and a total of 1467 patients were included in the final clinical analysis. Among the 1467 participants in this analysis, 910 (62.0%) were considered to the controlled group, 237 (16.2%) were considered to the uncontrolled group, and 320 (21.8%) were considered to the resistant group. Total follow‐up time was 1 year (Figure 1).
FIGURE 1.
Patient enrollment flow chart. CHD indicates coronary heart disease; Controlled group is defined as blood pressure of less than 140/90 mmHg while taking three or fewer antihypertensive medications; uncontrolled is defined as blood pressure of at least 140/90 mmHg while taking two or fewer antihypertensive medications; Resistant is defined as blood pressure not less than 140/90 mmHg on three antihypertensive drugs including diuretic or below 140/90 mmHg on at least four antihypertensive drugs.
3.2. Baseline characteristics
Baseline characteristics of all enrolled population and three subgroups based on hypertension control are summarized in Table 1. There were 1021 male (69.6%) and 446 females (30.4%) in all participants. Patients in the uncontrolled and resistant hypertension groups had higher average BMI than the controlled group. Interestingly, however, the average age of the uncontrolled group was higher than that of the controlled group, while the age of the resistant group was lower than that of the controlled and uncontrolled groups. Prevalence of baseline comorbidity including HF, LVH, and CKD was higher in patients with resistant group than in controlled and uncontrolled groups. Resistant group also had a higher proportion of baseline comorbidities of stroke/TIA, PAD, and diabetes compared with the controlled group. eGFR in patients with resistant group was lower than that in patients with uncontrolled and controlled groups. However, there was no significant difference in baseline TC and LDL cholesterol among the three groups.
TABLE 1.
Baseline characteristics of overall and subgroups in three groups of patients.
| Nonresistant hypertension (n = 1147) | |||||
|---|---|---|---|---|---|
| Variable | Total (n = 1467) | Controlled (n = 910) | Uncontrolled (n = 237) | Resistant hypertension (n = 320) | p value* |
| Age (years) | 60.48 ± 9.35 | 60.13 ± 9.43 | 62.54 ± 8.94+ | 59.97 ± 9.23# | .001 |
| Male (n, %) | 1021(69.6) | 635(69.8) | 153(64.6) | 233(72.8) # | .110 |
| BMI (kg/m2) | 26.77 ± 3.25 | 26.40 ± 3.06 | 27.22 ± 3.36+ | 27.47 ± 3.54+ | <.001 |
| Current smoking (n, %) | 360(24.5) | 218(24.0) | 48(20.3)+ | 94(29.4) # | .002 |
| Current drinking (n, %) | 261(17.8) | 151(16.6) | 45(19.0)+ | 65(20.3) # | .009 |
| Revascularization | 936(63.8) | 596(65.5) | 130(54.9) + | 210(65.6) # | .007 |
| Case history (n, %) | |||||
| MI | 292(20.0) | 180(19.8) | 36(15.2) | 77(24.1) # | .034 |
| HF | 83(5.7) | 38(4.2) | 9(3.8) | 36(11.3) +,# | <.001 |
| LVH by ECG a | 119(8.1) | 52(5.7) | 20(8.4) | 47(14.7) +,# | <.001 |
| Stroke/TIA | 237(16.2) | 133(14.6) | 42(17.7) | 62(19.4) + | .107 |
| PAD | 290(19.8) | 164(18.0) | 47(19.8) | 79(24.7) + | .036 |
| CKD b | 124(8.5) | 66(7.3) | 15(6.3) | 43(13.4) +,# | .001 |
| Diabetes | 593(40.4) | 337(37.0) | 100(42.2) | 156(48.8)+ | .001 |
| Number of antihypertensive medications (n, %) | 2.33 ± 0.95 | 2.05 ± 0.77 | 1.77 ± 0.45+ | 3.56 ± 0.59+,# | <.001 |
| Usage of medications (n, %) | |||||
| ACEI | 151(10.3) | 89(9.8) | 19(8.0) | 43(13.4) # | .081 |
| ARB | 900(61.3) | 491(54.0) | 151(63.7) + | 258(80.6) +,# | <.001 |
| β‐Blocker | 1140(77.7) | 696(76.5) | 156(65.8) + | 288(90.0) +,# | <.001 |
| Calcium channel blockers | 698(47.6) | 375(41.2) | 97(40.9) | 226(70.6) +,# | <.001 |
| Thiazide diuretics | 245(16.7) | 83(9.1) | 5(2.1) + | 157(49.1) +,# | <.001 |
| MRA | 219(14.9) | 104(11.4) | 0(0) + | 114(35.6) +,# | <.001 |
| Antiplatelet drugs | 1420(96.8) | 880(96.7) | 232(97.9) | 308(96.3) | .536 |
| Statin | 1444(98.4) | 898(98.7) | 233(98.3) | 313(97.8) | .553 |
| Laboratory variables | |||||
| TC (mmol/L) | 3.65 ± 0.98 | 3.62 ± 0.97 | 3.75 ± 1.00 | 3.67 ± 0.99 | .186 |
| LDL cholesterol (mmol/L) | 2.06 ± 0.81 | 2.03 ± 0.79 | 2.17 ± 0.87+ | 2.06 ± 0.79 | .064 |
| eGFR (mL/min/1.73 m2) | 86.81 ± 17.18 | 87.89 ± 16.83 | 88.05 ± 14.96 | 82.81 ± 19.10+,# | <.001 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitors; ARB, angiotensin II receptor blockers; BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; LDL, low density lipoprotein; LVH, left ventricular hypertrophy; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; TC, total cholesterol; TIA, transient ischemic attack; PAD, peripheral artery disease.
Defined as the sum of voltage amplitudes of SV1 and RV5 was equal to or greater than 3.5 mV according to the Sokolow–Lyon criterion.
Defined as eGFR < 60 mL/min/1.73 m2 on the basis of The KDIGO CKD Clinical Guideline.
Statistical significance was defined as p < .05. *For multiple comparisons. +Statistically significant versus controlled group. #Statistically significant versus uncontrolled group.
3.3. Blood pressure and antihypertensive drug use in three groups of patients
There were significant differences in usage of antihypertensive drugs between the three groups, with use of angiotensin II receptor blockers (ARB), β‐blockers, calcium channel blockers, thiazide diuretics, and mineralocorticoid receptor antagonist (MRA) significantly more common in patients with resistant group versus controlled and uncontrolled groups (Table 1). In the resistant group, the most commonly used antihypertensive drugs at baseline were β‐Blocker (90.0%), followed by ARB (80.6%), calcium channel blockers (70.6%), thiazide diuretics (49.1%), MRA (35.6%), and angiotensin‐converting enzyme inhibitors (ACEI) (13.4%). Figure 2 summarizes the types of antihypertensive drugs taken by the three groups of patients at discharge. However, a total of 877 patients in our study implemented ambulatory blood pressure monitoring during hospitalization, therefore, we only collected and analyzed the ambulatory blood pressure data of these patients. Both SBP and DBP at average values for 24‐h, daytime and nighttime ambulatory blood pressure were significantly higher when resistant group versus uncontrolled and controlled groups (Table 2).
FIGURE 2.
Percentage of three groups of hypertensive patients taking different antihypertensive drugs.
TABLE 2.
Baseline blood pressure of three groups of patients.
| Variable (mm Hg) | Total (n = 1467) | Controlled (n = 910) | Uncontrolled (n = 237) | Resistant (n = 320) | p value* |
|---|---|---|---|---|---|
| Office SBP | 134.05 ± 15.24 | 125.40 ± 9.18 | 149.34 ± 8.48+ | 147.33 ± 14.48+,# | <.001 |
| Office DBP | 82.34 ± 10.11 | 78.28 ± 7.54 | 89.79 ± 8.88+ | 88.37 ± 11.17+ | <.001 |
| 24‐h SBP | 128.21 ± 15.33 | 120.47 ± 10.34 | 139.81 ± 12.30+ | 137.43 ± 16.56+,# | <.001 |
| 24‐h DBP | 74.90 ± 10.11 | 71.50 ± 8.08 | 79.58 ± 9.71+ | 79.26 ± 11.57+ | <.001 |
| Daytime SBP | 128.66 ± 15.13 | 121.33 ± 10.75 | 139.64 ± 12.34+ | 137.36 ± 16.19+ | <.001 |
| Daytime DBP | 75.50 ± 10.30 | 72.25 ± 8.43 | 80.15 ± 10.03+ | 79.54 ± 11.63+ | <.001 |
| Nighttime SBP | 126.45 ± 18.54 | 117.21 ± 12.39 | 140.44 ± 15.34+ | 137.33 ± 20.20+ | <.001 |
| Nighttime DBP | 72.71 ± 11.01 | 68.86 ± 8.56 | 77.82 ± 10.38+ | 77.86 ± 12.88+ | <.001 |
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
Statistical significance was defined as p < .05. *For multiple comparisons. +Statistically significant versus controlled group. #Statistically significant versus uncontrolled group.
3.4. Baseline associated factors for resistant hypertension
We used stepwise logistic regression to identify variables that were highly correlated to resistant hypertension, with p < .1 as the cut‐off point into the model and p < .05 retained in the final model. Finally, there are eight variables including BMI, smoking, HF, LVH, stroke/TIA, PVD, diabetics, and CKD statistically associated with resistant hypertension, and finally entered the multiple adjusted logistic regression analysis model. The results showed that per unit changes BMI (OR, 1.12 [95% CI, 1.07–1.16], p < .001) and four categorical variables diagnosis by yes or no: HF (OR, 2.62 [95% CI, 1.58–4.36], p < .001), LVH (OR, 2.83 [95% CI, 1.83–4.39], p < .001), diabetes (OR, 1.55 [95% CI, 1.16–2.07], p = .003), and CKD (OR, 1.61 [95% CI, 1.05–2.48], p = .030) were associated factors with increased risk of resistant hypertension (Table 3, Figure 3).
TABLE 3.
Logistic regression with the clinical variables associated with resistant hypertension versus controlled hypertension.
| Parameter | Unadjusted | Adjusted a | ||
|---|---|---|---|---|
| OR (95%CI) | p | OR (95%) | p | |
| BMI (per 1‐kg/m2 increment) | 1.11(1.06–1.15) | <.001 | 1.12(1.07–1.16) | <.001 |
| Smoking (vs. no) | 1.16(0.84–1.61) | .036 | NS | .165 |
| HF (vs. no) | 2.91(1.81–4.68) | <.001 | 2.62(1.58–4.36) | <.001 |
| LVH (vs. no) | 2.84(1.87–4.31) | <.001 | 2.83(1.83–4.39) | <.001 |
| Stroke/TIA (vs. no) | 1.40(1.01–1.96) | .046 | NS | .337 |
| PVD (vs. no) | 1.49(1.10–2.02) | .010 | NS | .639 |
| Diabetics (vs. no) | 1.62(1.25–2.09) | <.001 | 1.55(1.16–2.07) | 0.003 |
| CKD (vs. no) | 1.99(1.32–2.98) | .001 | 1.61(1.05–2.48) | .030 |
Abbreviations: BMI, body mass index; CKD, chronic kidney disease; HF, heart failure; LVH, left ventricular hypertrophy; NS, not significant; OR, odds ratio; PVD, peripheral vascular disease; TIA, transient ischemic attack.
Adjusted for BMI, smoking, HF, LVH, Stroke/TIA, PVD, diabetes, and CKD. Statistical significance was defined as p < .05.
FIGURE 3.
Baseline association factors with resistant hypertension. BMI, body mass index; CKD, chronic kidney disease; HF, heart failure; LVH, left ventricular hypertrophy.
3.5. Clinical outcomes and endpoint events
During the 1‐year follow‐up period, a total of 154 (10.5%) primary endpoint events were recorded, including 13 (0.9%) all‐cause mortality, 129 (8.8%) ASCVD events, and 12 (0.8%) HF events. The primary endpoint events included 71 (7.8%) events in the controlled group, 26 (11.0%) in the uncontrolled group, and 57 (17.8%) in the resistant group (Table 4). The cumulative incidence of primary endpoint, ASCVD, and HF events was significantly higher in the resistant group than in the controlled group (Table 4, Figure 4). Compared with the controlled group, the unadjusted HR for primary endpoint events in resistant group and uncontrolled group were 2.43 (95% CI 1.72–3.45, p < .001) and 1.39 (95% CI, 0.88–2.18, p > .05), respectively. There were significant differences in cumulative incidence of primary endpoint among the three groups (overall log‐rank p < .0001; Figure 4A). However, there was no difference between the uncontrolled and controlled group (log‐rank p > .05; Figure 4A). After adjusting by confounding factors including age, sex, BMI, smoking, and diabetes, the HR for primary endpoint events in resistant group and uncontrolled group were 2.35 (95% CI 1.65–3.35, p < .001) and 1.42 (95% CI 0.90–2.23, p > .05; Table 4), respectively. In the final multiple adjusted analyses, patients in the resistant group had a higher risk of the primary endpoint events (HR 2.14; 95% CI 1.47–3.11, p < .001) comparing with the controlled group (Table 4). Moreover, there were significant differences in secondary outcomes ASCVD events among the three groups (overall log‐rank p = .002; Figure 4B), patients in the resistant group had a higher risk of ASCVD (HR 2.11, 95% CI 1.39–3.20, p < .001) comparing with the controlled group (Table 4).
TABLE 4.
Risks associated with resistant and uncontrolled groups for occurrence of composite and individual event.
| Outcomes | N (%) | Model 1 a | Model 2 b | Model 3 c |
|---|---|---|---|---|
| HR (95%) | HR (95%) | HR (95%) | ||
| Primary endpoint events | 154(10.5) | |||
| Controlled | 71(7.8) | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| Uncontrolled | 26(11.0) | 1.43(0.92–2.25) | 1.42(0.90–2.23) | 1.41(0.87–2.29) |
| Resistant | 57(17.8) | 2.43(1.72–3.45)*** | 2.35(1.65–3.35)*** | 2.14(1.47–3.11)*** |
| All‐cause mortality | 13(0.9) | |||
| Controlled | 7(0.8) | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| Uncontrolled | 1(0.4) | NA | NA | NA |
| Resistant | 5(1.6) | 0.41(0.10–1.69) | 1.15(0.09–15.69) | NA |
| ASCVD events | 129(8.8) | |||
| Controlled | 60(6.6) | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| Uncontrolled | 25(10.5) | 1.65(1.03–2.63)* | 1.63(1.01–2.61)* | 1.61(0.97–2.67) |
| Resistant | 44(13.8) | 2.19(1.48–3.23)*** | 2.10(1.41–3.11)*** | 2.11(1.39–3.20)*** |
| HF events | 12(0.8) | |||
| Controlled | 4(0.4) | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| Uncontrolled | 0 | NA | NA | NA |
| Resistant | 8(2.5) | 5.73(1.73–19.04)** | 5.95(1.76–20.06)** | 3.49(0.92–13.22) |
Note: The values describe HR (95% CIs).
Abbreviations: ASCVD, atherosclerotic cardiovascular disease, defined as stroke/TIA or CHD events; BMI, body mass index; CVDs, cardiovascular diseases; eGFR, estimated glomerular filtration rate; HF, heart failure, defined as requiring hospitalization and treatment due to clinical manifestations of HF; HR, hazard ratio; LDL, low‐density lipoprotein; MI, myocardial infarction; TC, total cholesterol; TIA, transient ischemic attack.
Model 1 was unadjusted model.
Model 2 was adjusted by confounding factors including age, sex, BMI, smoking, diabetes.
Model 3 was further adjusted for TC, LDL cholesterol, eGFR, statin use, established CVDs including MI, stroke/TIA, and HF, and revascularization therapy (ever and during this hospitalization).
* p < .05, ** p < .01, *** p < .001.
FIGURE 4.
Cumulative incidence of total and ASCVD events in three hypertension groups. Kaplan–Meier curves showing the cumulative incidence of total events (A) and ASCVD events (B) in patients with controlled, uncontrolled, and resistant groups. Total events were defined as first occurrence of the all‐cause mortality or nonfatal CVD events (including stroke/TIA, CHD, and HF); ASCVD was defined as occurrence of stroke/TIA or CHD. ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; HF, heart failure; TIA, transient ischemic attack.
4. DISCUSSION
We analyzed a prospective, observational clinical study of 1467 hypertensive patients who had developed CHD, and demonstrated that resistant hypertension was a quite common and high proportion finding (21.8%) in central region of China. Up to now, there are few studies on the prevalence of resistant hypertension in patients with CHD and hypertension in China. To our knowledge, this is the first study to investigate the effect of clinical outcomes in patients with resistant hypertension and CHD in central region of China. Interestingly, we found that patients with resistant hypertension had a significantly increased risk of adverse cardiovascular outcomes compared to those with controlled hypertension, mainly in overall events and ASCVD events.
With reference to some clinical trials, the accurate prevalence of resistant hypertension in hypertensive patients is difficult to determine, accounting for about 12%–46%. The main influencing factors are the instability of the hypertensive population in the study, the different ways of blood pressure measurement and different definitions of resistant hypertension (the main difference is whether the three drugs must contain diuretics). 6 , 7 , 11 , 21 Furthermore, resistant hypertension often does not exist alone in patients, and it usually has a high proportion of comorbidities, including diabetes and target organ damage (LVH, cardiac insufficiency, and renal dysfunction) were more common in patients with true resistant hypertension, 11 , 22 , 23 and our findings also provide evidence for this phenomenon. In addition, BMI was significantly associated with resistant hypertension, which has been confirmed in previous and our studies. 8 , 11 , 15 , 23 , 24 , 25 However, both our study and the ASCOT trial showed that age is not associated with resistant hypertension, 26 which is different from the INVEST study. 11 Furthermore, interestingly, the relationship between older age and women and resistant hypertension is uncertain. Some studies have shown that patients with resistant hypertension are older and female, 11 , 27 but some studies do not fully have the above characteristics. 8 , 15 , 23 , 25 , 28 In our study, resistant hypertension were more common in younger male patients, which is consistent with recent findings of resistant hypertension diagnosed with ambulatory blood pressure monitoring. 25 This uncertainty may be due to differences in disease types and sex bias in the study participants.
Results of our present study means that patients with CHD with resistant hypertension have a worse clinical prognosis than patients with controlled hypertension, which is consistent with previous large clinical trials. 11 , 24 , 25 , 27 , 28 A large number of large sample size clinical studies have shown that resistant hypertension, whether assessed and defined based on office blood pressure measurement, home self‐test blood pressure, or ambulatory blood pressure monitoring, is an independent significant risk factor of long‐term adverse cardiovascular events. 8 , 11 , 15 , 24 , 25 , 27 , 28 , 29 , 30 In INVEST study, patients with resistant hypertension had a higher risk of major adverse outcomes than those in the controlled hypertension group (HR 1.27; 95% CI 1.13–1.43; p < .05). Our findings once again provide evidence for the adverse effects of resistant hypertension in patients diagnosed with CHD following the INVEST study. We differed from the INVEST trial in the definition of the primary outcome and the duration of follow‐up, and therefore could not further compare the rates and risk of combined and individual adverse cardiovascular events. Regardless, we still consider that our findings to be an important addition to the field in central region China.
At present, the potential mechanism of resistant hypertension increasing the risk of cardiovascular disease is not clear. It is considered to be the result of the interaction of multiple processes. Firstly, three large clinical trials (INVEST, REGARDS, and REACH) 8 , 11 , 28 , 31 all demonstrated that differences in blood pressure control among patients with resistant hypertension were not associated with differences in cardiovascular outcomes, suggesting that differences in baseline blood pressure control cannot alone explain the increased risk of recurrent MACE and increased all‐cause mortality. Other than that, due to the need to take three or more antihypertensive drugs in patients with resistant hypertension, patients often have poor compliance, which maybe an important cause of poor cardiovascular prognosis, and is also the main cause of treatment failure and repeated hospitalization. 32 Last but not least, patients with resistant hypertension involve complex pathophysiological mechanisms, including but not limited to increased renal‐angiotensin system and sympathetic nervous system activity, increased aldosterone and increased atherosclerosis in patients with resistant hypertension, which may be related to increased cardiovascular risk. 11 , 22 , 28
The results of UCC‐SMART trial showed that at the age of 50, compared with patients without resistant hypertension, the median life expectancy of patients with resistant hypertension was reduced by an average of 4.1 years. 28 Also, a recent meta‐analysis also found that the effect of antihypertensive therapy on cardiovascular risk was closely related to the degree of SBP reduction. In addition, regardless of baseline blood pressure, regardless of cardiovascular history, a 5‐mmHg reduction in SBP reduces the overall risk of major cardiovascular events by approximately 10%. 33 The above data show that it is particularly important to identify and actively control blood pressure in patients with resistant hypertension in clinical work. Therefore, it is a global and long‐term laborious duty to continue to explore other effective means to reduce blood pressure and effectively reduce cardiovascular prognosis in addition to antihypertensive drugs.
The strengths of our study present are that it fills in the impact of resistant hypertension on cardiovascular prognosis in patients with CHD in central region of China. It is a prospective, observational clinical study with a low rate of loss of follow‐up (5.1%). Overall, we observed that patients with resistant hypertension have worse cardiovascular prognosis than those with controllable hypertension. Although there are important discoveries revealed by these studies, there are also limitations. Firstly, this is a single‐center clinical trial with insufficient sample size and limited follow‐up time. The results of the study are limited to the central region of China and cannot represent the overall level of China. Therefore, the assessment of the prevalence of resistant hypertension and the clinical outcomes of patients with CHD with controlled or uncontrolled hypertension may be inaccurate. Secondly, not all patients in our study had implemented ambulatory blood pressure monitoring, so it may not be enough to rule out all white coat hypertension, and thus may not avoid the possibility of dividing some patients using only clinic blood pressure. Finally, because the uncontrolled group did not receive adequate antihypertensive drug treatment, it may also affect the prevalence of resistant hypertension and the statistical differences in some data between the three groups. However, we believe that these problems could be solved if we continue to expand the sample size and extend the follow‐up period in the future.
AUTHOR CONTRIBUTIONS
Binbin Zhu and Yahui Liu: Study design, collection of data, statistical analyses, drafting of the manuscript. Weicen Zhou, Yao Du, and Chenxu Wang: Collection of data, statistical analyses. Datun Qi: Study design, critical revision for important intellectual content. Qianqian Cheng, You Zhang, and Shan Wang: Collection of data, statistical analyses. Chuanyu Gao: Study conception and design, critical revision for important intellectual content, and final approval of the submitted manuscript.
CONFLICT OF INTEREST STATEMENT
All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
ACKNOWLEDGMENTS
The authors have nothing to report.
Zhu B, Liu Y, Zhou W, et al. Clinical characteristics and outcomes of Chinese patients with coronary heart disease and resistant hypertension. J Clin Hypertens. 2023;25:350–359. 10.1111/jch.14651
Binbin Zhu and Yahui Liu contributed equally to this work.
DATA AVAILABILITY STATEMENT
The date that supports the findings of this study are available from the corresponding author upon reasonable request. The date is not publicly due to them containing information that could compromise research participant privacy.
REFERENCES
- 1. Al‐Makki A, DiPette D, Whelton PK, et al. Hypertension pharmacological treatment in adults: a world health organization guideline executive summary. Hypertension (Dallas, Tex: 1979). 2022;79(1):293‐301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Zhou B, Perel P, Mensah GA, Ezzati M. Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nat Rev Cardiol. 2021;18(11):785‐802. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Hisamatsu T, Segawa H, Kadota A, Ohkubo T, Arima H, Miura K. Epidemiology of hypertension in Japan: beyond the new 2019 Japanese guidelines. Hypertens Res. 2020;43(12):1344‐1351. [DOI] [PubMed] [Google Scholar]
- 4. Kario K, Wang JG. Could 130/80 mm Hg be adopted as the diagnostic threshold and management goal of hypertension in consideration of the characteristics of Asian populations? Hypertension (Dallas, Tex: 1979). 2018;71(6):979‐984. [DOI] [PubMed] [Google Scholar]
- 5. Carey RM, Calhoun DA, Bakris GL, et al. resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension (Dallas, Tex: 1979). 2018;72(5):e53‐e90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011;124(9):1046‐1058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension (Dallas, Tex: 1979). 2011;57(6):1076‐1080. [DOI] [PubMed] [Google Scholar]
- 8. Kumbhani DJ, Steg PG, Cannon CP, et al. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis. Eur Heart J. 2013;34(16):1204‐1214. [DOI] [PubMed] [Google Scholar]
- 9. Chun KH, Lee CJ, Oh J, et al. Prevalence and prognosis of the 2018 vs 2008 AHA definitions of apparent treatment‐resistant hypertension in high‐risk hypertension patients. J Clin Hypertens (Greenwich). 2020;22(11):2093‐2102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Li D, Huo Z, Liu D, et al. Current apparent treatment‐resistant hypertension in patients undergoing peritoneal dialysis: a multi‐center cross‐sectional study. J Clin Hypertens (Greenwich). 2022;24(4):493‐501. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32(3):635‐643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Muntner P, Davis BR, Cushman WC, et al. Treatment‐resistant hypertension and the incidence of cardiovascular disease and end‐stage renal disease: results from the antihypertensive and lipid‐lowering treatment to prevent heart attack trial (ALLHAT). Hypertension (Dallas, Tex: 1979). 2014;64(5):1012‐1021. [DOI] [PubMed] [Google Scholar]
- 13. Ohman EM, Bhatt DL, Steg PG, et al. The REduction of Atherothrombosis for Continued Health (REACH) registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events‐study design. Am Heart J. 2006;151(4):786.e781‐710. [DOI] [PubMed] [Google Scholar]
- 14. Lu J, Lu Y, Wang X, et al. Prevalence, awareness, treatment, and control of hypertension in China: data from 1.7 million adults in a population‐based screening study (China PEACE Million Persons Project). Lancet (London, England). 2017;390(10112):2549‐2558. [DOI] [PubMed] [Google Scholar]
- 15. Kario K, Hoshide S, Narita K, Okawara Y, Kanegae H. Cardiovascular prognosis in drug‐resistant hypertension stratified by 24‐hour ambulatory blood pressure: the JAMP study. Hypertension (Dallas, Tex: 1979). 2021;78(6):1781‐1790. [DOI] [PubMed] [Google Scholar]
- 16. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127‐e248. [DOI] [PubMed] [Google Scholar]
- 17. Pepine CJ, Handberg EM, Cooper‐DeHoff RM, et al. A calcium antagonist vs a non‐calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil‐Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21):2805‐2816. [DOI] [PubMed] [Google Scholar]
- 18. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604‐612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825‐830. [DOI] [PubMed] [Google Scholar]
- 20. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J. 1949;37(2):161‐186. [DOI] [PubMed] [Google Scholar]
- 21. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid‐lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4(6):393‐404. [DOI] [PubMed] [Google Scholar]
- 22. Acelajado MC, Hughes ZH, Oparil S, Calhoun DA. Treatment of resistant and refractory hypertension. Circ Res. 2019;124(7):1061‐1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Oliveras A, de la Sierra A. Resistant hypertension: patient characteristics, risk factors, co‐morbidities and outcomes. J Hum Hypertens. 2014;28(4):213‐217. [DOI] [PubMed] [Google Scholar]
- 24. Bangalore S, Fayyad R, Laskey R, et al. Prevalence, predictors, and outcomes in treatment‐resistant hypertension in patients with coronary disease. Am J Med. 2014;127(1):71‐81.e71. [DOI] [PubMed] [Google Scholar]
- 25. Narita K, Hoshide S, Kario K. Association of treatment‐resistant hypertension defined by home blood pressure monitoring with cardiovascular outcome. Hypertens Res. 2022;45(1):75‐86. [DOI] [PubMed] [Google Scholar]
- 26. Gupta AK, Nasothimiou EG, Chang CL, et al. Baseline predictors of resistant hypertension in the Anglo‐Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high‐risk. J Hypertens. 2011;29(10):2004‐2013. [DOI] [PubMed] [Google Scholar]
- 27. van der Sande NGC, de Beus E, Bots ML, et al. Apparent resistant hypertension and the risk of vascular events and mortality in patients with manifest vascular disease. J Hypertens. 2018;36(1):143‐150. [DOI] [PubMed] [Google Scholar]
- 28. Groenland EH, Bots ML, Asselbergs FW, et al. Apparent treatment resistant hypertension and the risk of recurrent cardiovascular events and mortality in patients with established vascular disease. Int J Cardiol. 2021;334:135‐141. [DOI] [PubMed] [Google Scholar]
- 29. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635‐1642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Sim JJ, Bhandari SK, Shi J, et al. Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension. Kidney Int. 2015;88(3):622‐632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Irvin MR, Booth JN, Shimbo D, et al. Apparent treatment‐resistant hypertension and risk for stroke, coronary heart disease, and all‐cause mortality. J Am Soc Hypertens. 2014;8(6):405‐413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Lamirault G, Artifoni M, Daniel M, Barber‐Chamoux N. Nantes university hospital working group on H. resistant hypertension: novel insights. Curr Hypertens Rev. 2020;16(1):61‐72. [DOI] [PubMed] [Google Scholar]
- 33. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant‐level data meta‐analysis. Lancet (London, England). 2021;397(10285):1625‐1636. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The date that supports the findings of this study are available from the corresponding author upon reasonable request. The date is not publicly due to them containing information that could compromise research participant privacy.