Safety of Calcium Channel Blockers in Patients With Severe Aortic Stenosis and Hypertension

Abstract

Background: There is a paucity of data on safety of calcium channel blockers (CCB) in patients with severe aortic stenosis (AS) and hypertension.

Methods and Results: Among 2,460 patients with severe AS and hypertension receiving antihypertensive therapy in the CURRENT AS registry-2, we compared the clinical outcomes between patients taking antihypertensive therapy with CCB (CCB group) and without CCB (no CCB group). In the entire study population, CCB was prescribed in 1,763 patients (71.7%), which was the most commonly prescribed antihypertensive agents. The prescription rates of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and thiazides were 61.9%, 25.6%, and 7.3% in the CCB group, and 75.8%, 54.4%, and 6.0% in the no CCB group. In the propensity score matched cohort, the cumulative 3-year incidence of all-cause death or hospitalization for heart failure was not different between the CCB and no CCB groups (38.3% vs. 38.7%, log-rank P=0.65; HR, 0.94; 95%CI, 0.77–1.15; P=0.56). The cumulative 3-year incidence of syncope was low regardless of CCB prescription (1.1% vs. 1.0%, P=0.74).

Conclusions: Among patients with severe AS and hypertension, CCB was the most commonly prescribed antihypertensive agents, and antihypertensive therapy with CCB was associated with comparable clinical outcomes to antihypertensive therapy without CCB. Syncope was rarely seen in patients with severe AS and hypertension receiving antihypertensive therapy regardless of CCB prescription.

Hypertension was common comorbidity in patients with aortic stenosis (AS), with previous studies reporting that hypertension was associated with abnormal left ventricular (LV) structure and poor prognosis in patients with AS.^1–5 US and European clinical guidelines recommend antihypertensive therapy in patients with AS and hypertension; however, there is a paucity of evidence comparing different types of antihypertensive therapy in patients with AS and hypertension.^6–10 On the basis of positive results from very small randomized controlled trials (RCTs) and observational studies in patients with AS and hypertension, a European consensus document recommends the use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) as first-line therapy, with the addition of β-blockers, if needed.¹ Conversely, calcium channel blockers (CCBs), which are the most commonly used antihypertensive agents in the general hypertensive population, are not regarded as first-line treatment because of the scarcity of studies evaluating CCBs and clinical outcomes in patients with AS and hypertension.^1,2 There are concerns regarding the use of CCBs in patients with severe AS in real-world clinical practice, such as an excessive fall in blood pressure (BP) resulting from antihypertensive therapy-induced vasodilation combined with reduced stroke volume due to aortic valve obstruction, and the safety of using CCBs in patients with severe AS and hypertension is unknown.^1,2 Therefore, in this study we evaluated the safety and efficacy of antihypertensive therapy with CCBs in patients with severe AS and hypertension using a large-scale Japanese multicenter registry of patients with severe AS.

Methods

Study Design and Population

CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) Registry-2 is a prospective physician-initiated non-company sponsored multicenter registry that enrolled consecutive patients who were diagnosed with severe AS between April 2018 and December 2020 at 21 participating centers in Japan (Supplementary Appendix 1). Details of the CURRENT AS Registry-2 have been reported elsewhere.^11,12 Patients with severe AS were defined as those who met at least 1 of the 3 echocardiographic criteria (peak aortic jet velocity >4.0 m/s, mean aortic pressure gradient >40 mmHg, or aortic valve area [AVA] <1.0 cm²). Patients who had a history of aortic valve surgery or percutaneous aortic balloon valvuloplasty were excluded. Initial treatment strategies (initial aortic valve replacement [AVR] or conservative management) were determined through discussion between attending physicians and patients, with occasional consultation with the heart team. The choice between surgical AVR (SAVR) and transcatheter aortic valve implantation (TAVI) was based on a consensus reached within the heart team and patient preferences. The follow-up period started on the day of the index echocardiography.

This study was performed in accordance with the Declaration of Helsinki and the study protocol was approved by the institutional review boards of all 21 participating centers. Written informed consent was obtained from each patient at 19 centers, whereas the remaining 2 centers used the opt-out strategy, which waived the requirement for written informed consent, with the permission of their institutional review boards.

In this study we compared baseline characteristics and clinical outcomes among patients with severe AS and hypertension who were receiving antihypertensive therapy either with or without CCBs. Hypertension was defined as systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg, or a history of hypertension; antihypertensive therapy was defined as any of the following medications: CCB, ACEi, ARB, β-blockers, or thiazides (including thiazide-type diuretics).^6,7,10 Patients who were prescribed CCB, ACEi, ARB, β-blockers, or thiazides but did not meet the definition of hypertension were excluded from this study (n=618). In addition, we excluded 3 patients for whom antihypertensive therapy data were not available, as well as another 288 patients with hypertension who were not receiving antihypertensive therapy. Thus, the present study population consisted of 2,460 patients with severe AS and hypertension receiving antihypertensive therapy from the 3,369 patients enrolled in the CURRENT AS Registry-2 (Figure 1).

Figure 1.

Study flowchart. AS, aortic stenosis; AVR, aortic valve replacement; CCB, calcium channel blockers; CURRENT AS, Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis.

Outcome Measure

The primary outcome measure in this study was a composite of all-cause death or hospitalization for heart failure. Hospitalization for heart failure was defined as hospitalization due to worsening heart failure requiring intravenous drug therapy. Secondary outcome measures included all-cause death, cardiovascular death, non-cardiovascular death, aortic valve-related death, sudden death, hospitalization for heart failure, stroke, disabling stroke, syncope, and a composite of syncope or presyncope. Syncope was defined as a transient loss of consciousness due to cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous complete recovery.¹² Presyncope was defined as a state that resembled the prodrome of syncope but was not followed by loss of consciousness.¹³ Detailed definitions of secondary outcome measures are provided in the Supplementary Appendix 3. A clinical event committee adjudicated the causes of death and stroke according to Valve Academic Research Consortium 3 criteria.¹⁴

Statistical Analysis

Categorical variables are presented as numbers and percentages and were compared using the Chi-squared test or Fisher’s exact test. Continuous variables are expressed as the mean±SD or median with interquartile range (IQR) and were compared using Student’s t-test or the Wilcoxon rank-sum test depending on the normality of their distribution. Cumulative incidences were estimated by the Kaplan-Meier method, in which the time of the index echocardiography was regarded as Time 0, and the significance of differences was assessed using the log-rank test. We performed the propensity score (PS) matching analyses as the main analyses to adjust potential confounders. A logistic regression model was used to develop PSs with 22 independent variables relevant to choosing antihypertensive therapy with CCB (age, male sex, current smoking, diabetes on insulin therapy, prior myocardial infarction, prior symptomatic stroke, atrial fibrillation or flutter, aortic and/or peripheral vascular disease, creatinine >2 mg/dL not hemodialysis, hemodialysis, coronary artery disease, Clinical Frailty Scale score ≤4, syncope, heart failure, New York Heart Association Class IV, peak aortic jet velocity [V_max] >4 m/s, LV ejection fraction [LVEF] <50%, tricuspid regurgitation pressure gradient ≥40 mmHg, any combined valvular disease, initial AVR strategy, ACEi/ARB, and β-blockers). Patients in the CCB group were matched to those in the no CCB group using a 1 : 1 greedy matching technique to create the PS-matched cohort. The distribution of PSs before and after matching is shown in Supplementary Figure 1.

The effects of using CCBs (CCB group) relative to not using CCBs (no CCB group) on outcome measures are expressed as hazard ratios (HRs) and 95% confidence intervals (CIs) estimated by the Cox proportional hazard models incorporating participating center as a stratification variable. We also performed subgroup analyses stratified by the initial treatment strategy (initial AVR or conservative management), age (≥80 vs. <80 years), or V_max (>4 vs. ≤4 m/s) for the primary outcome measure, as well as all-cause death and hospitalization for heart failure in the PS-matched cohort.

As a sensitivity analysis, we constructed multivariable Cox proportional hazard models with the potential confounders as the adjusted variables in the entire study population. Detailed methods for the multivariable analyses are presented in the Supplementary Methods. Furthermore, to evaluate the characteristics of patients with severe AS and hypertension receiving antihypertensive therapy who experienced syncope during follow-up, we compared baseline characteristics between patients with and without syncope during follow-up in the entire study population. Multivariable analysis evaluating the association between baseline characteristics and syncope was not performed due to very small number of patients with syncope during follow-up.

All reported P values are 2-sided and P<0.05 was considered statistically significant. All analyses were performed with R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Antihypertensive Therapy

Of the 2,460 study patients, 1,763 (71.7%) patients were prescribed CCBs, which was the most common antihypertensive therapy (Table 1). The second most common antihypertensive therapy was ACEi/ARB (65.9%), followed by β-blockers (33.8%). The median number of different antihypertensive therapy class drugs was 2 (IQR 1–2). The prescription rates of ACEi/ARB, β-blockers, and thiazides were 61.9%, 25.6%, and 7.3%, respectively, in the CCB group, and 75.8%, 54.4%, and 6.0%, respectively, in the no CCB group.

Table 1.

Details of Antihypertensive Therapy

	Entire study population (n=2,460)	CCB group (n=1,763)	No CCB group (n=697)
CCB use	1,763 (71.7)	1,763 (100)	0 (0)
ACEi/ARB use	1,620 (65.9)	1,092 (61.9)	528 (75.8)
ACEi use	275 (11.2)	144 (8.2)	131 (18.8)
ARB use	1,372 (55.8)	971 (55.1)	401 (57.5)
β-blocker use	831 (33.8)	452 (25.6)	379 (54.4)
Thiazide use	171 (7.0)	129 (7.3)	42 (6.0)
No. antihypertensive drug therapy classes	2 [1–2]	2 [1–2]	1 [1–2]
One	941 (38.3)	486 (27.6)	455 (65.3)
CCB only	486 (19.8)	486 (27.6)	0 (0)
ACEi/ARB only	290 (11.8)	0 (0)	290 (41.6)
β-blockers only	158 (6.4)	0 (0)	158 (22.7)
Thiazides only	7 (0.3)	0 (0)	7 (1.0)
Two	1,137 (46.2)	905 (51.3)	232 (33.3)
CCB + ACEi/ARB	728 (29.6)	728 (41.3)	0 (0)
CCB + β-blocker	163 (6.6)	163 (9.2)	0 (0)
CCB + thiazide	14 (0.6)	14 (0.8)	0 (0)
ACEi/ARB + β-blocker	207 (8.4)	0 (0)	207 (29.7)
ACEi/ARB + thiazide	21 (0.9)	0 (0)	21 (3.0)
β-blocker + thiazide	4 (0.2)	0 (0)	4 (0.6)
Three	358 (14.6)	348 (19.7)	10 (1.4)
CCB + ACEi/ARB + β-blocker	257 (10.4)	257 (14.6)	0 (0)
CCB + ACEi/ARB + thiazide	83 (3.4)	83 (4.7)	0 (0)
CCB + β-blocker + thiazide	8 (0.3)	8 (0.5)	0 (0)
ACEi/ARB + β-blocker + thiazide	10 (0.4)	0 (0)	10 (1.4)
Four	24 (1.0)	24 (1.4)	0 (0)
CCB + ACEi/ARB + β-blocker + thiazide	24 (1.0)	24 (1.4)	0 (0)

Categorical variables are presented as n (%). Continuous variables are presented as the median [interquartile range]. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.

Baseline Characteristics

In the entire study population, the mean age of patients was 82.0 years, 39.5% were men, and 59.1% had symptomatic severe AS. The prevalence of high-gradient AS was 57.4%, and an initial AVR strategy was selected for 51.7% of patients.

Compared with the no CCB group, the CCB group was less likely to have low body weight, a history of myocardial infarction, atrial fibrillation or flutter, frailty, and heart failure, but more likely to have dyslipidemia (Supplementary Table 1). On echocardiography, the CCB group had a lower V_max, mean aortic pressure gradient, LVEF, and stroke volume index than the no CCB group (Supplementary Table 1). The prevalence of high-gradient AS and any combined valve disease was lower in the CCB than no CCB group. In terms of medications other than antihypertensive therapy, the prescription rate of oral anticoagulants was lower in the CCB than no CCB group (Supplementary Table 1). There was no significant difference in the initial treatment strategy selected between the 2 groups (Supplementary Table 1). The respectively incidence of AVR (SAVR or TAVI) in the CCB and no CCB groups was 60.2% and 60.5% at 1 year, 68.9% and 68.7% at 2 years, and 75.9% and 73.8% at 3 years (log-rank P=0.75; Supplementary Figure 2).

After PS matching, there were 643 patients each in the CCB and no CCB groups (Figure 1). In the PS-matched cohort, the clinical and echocardiographic characteristics of CCB and no CCB groups were generally comparable, other than body mass index (Table 2). The mean AVA and LVEF differed significant between the 2 groups, but the prevalence of AVA <1.0 cm², LVEF <40%, and LVEF <50% did not different between the 2 groups in the PS-matched cohort (Table 2).

Table 2.

Baseline Characteristics in the Propensity Score-Matched Cohort

	CCB group (n=643)	No CCB group (n=643)	P value	SMD
Clinical characteristics
Age (years)	81.5±8.1	81.9±8.4	0.30	0.06
Age ≥80 years	424 (65.9)	426 (66.3)	0.91	0.01
Male sex	272 (42.3)	257 (40.0)	0.40	0.05
BMI (kg/m2)	23.5±3.8	22.5±3.8	<0.001	0.28
BMI <22.0 kg/m2	241 (37.5)	305 (47.4)	<0.001	0.20
BSA (m2)	1.6±0.2	1.5±0.2	<0.001	0.22
Current smoking	23 (3.6)	22 (3.4)	0.88	0.01
Dyslipidemia	372 (57.9)	345 (53.7)	0.13	0.09
Diabetes	207 (32.2)	202 (31.4)	0.77	0.02
On insulin therapy	24 (3.7)	27 (4.2)	0.67	0.02
Prior MI	61 (9.5)	70 (10.9)	0.41	0.05
Prior open heart surgery	13 (2.0)	19 (3.0)	0.28	0.06
Prior symptomatic stroke	85 (13.2)	102 (15.9)	0.18	0.08
Atrial fibrillation or flutter	195 (30.3)	206 (32.0)	0.51	0.04
Aortic and/or peripheral vascular disease	44 (6.8)	53 (8.2)	0.34	0.05
Creatinine >2 mg/dL or hemodialysis	85 (13.2)	82 (12.8)	0.80	0.01
Creatinine >2 mg/dL, not hemodialysis	28 (4.4)	32 (5.0)	0.60	0.03
Hemodialysis	57 (8.9)	50 (7.8)	0.48	0.04
Anemia	340 (52.9)	356 (55.4)	0.37	0.05
Liver cirrhosis (Child B or C)	4 (0.6)	7 (1.1)	0.36	0.05
Malignancy	118 (18.4)	111 (17.3)	0.61	0.03
Malignancy currently under treatment	32 (5.0)	40 (6.2)	0.33	0.05
Chest wall irradiation	5 (0.8)	6 (0.9)	0.76	0.02
Immunosuppressive therapy	26 (4.0)	39 (6.1)	0.10	0.09
Chronic lung disease (moderate or severe)	46 (7.2)	38 (5.9)	0.37	0.05
Coronary artery disease	240 (37.3)	250 (38.9)	0.57	0.03
Clinical Frailty Scale score			0.12	0.12
1–3	300 (46.7)	308 (47.9)
4–6	311 (48.4)	287 (44.6)
7–9	32 (5.0)	48 (7.5)
Clinical Frailty Scale score ≤4	469 (72.9)	468 (72.8)	0.95	0.003
Presentation
Etiology			0.42	0.07
Degenerative	607 (94.4)	597 (92.8)
Congenital (uni-, bi-, or quadricuspid)	31 (4.8)	37 (5.8)
Rheumatic	5 (0.8)	9 (1.4)
Infective endocarditis	0 (0)	0 (0)
Symptoms
Any symptoms probably related to AS	419 (65.2)	417 (64.9)	0.91	0.01
Chest pain	58 (13.8)	50 (12.0)	0.43	0.06
Syncope	28 (6.7)	42 (10.1)	0.08	0.12
HF	381 (90.9)	378 (90.6)	0.89	0.01
NYHA functional class			0.18	0.13
II	256 (67.2)	234 (61.9)
III	83 (21.8)	104 (27.5)
IV	42 (11.0)	40 (10.6)
HF hospitalization at index echocardiography	71 (11.0)	70 (10.9)	0.93	0.01
Echocardiography
Vmax (m/s)	4.1±0.8	4.1±0.9	0.83	0.01
Vmax >4 m/s	321 (49.9)	332 (51.6)	0.54	0.03
Vmax >5 m/s	77 (12.0)	96 (14.9)	0.12	0.09
Mean aortic PG (mmHg)	39.4±16.7	40.0±18.1	0.52	0.04
Mean aortic PG >40 mmHg	265 (41.4)	269 (42.0)	0.84	0.01
AVA (cm2)	0.8±0.2	0.7±0.2	0.01	0.15
AVA <1.0 cm2	620 (96.7)	628 (97.8)	0.23	0.07
AVA index (cm2/m2)	0.5±0.1	0.5±0.1	0.49	0.04
LVEF (%)	60.4±11.3	58.8±11.3	0.01	0.14
LVEF <40%	44 (6.8)	51 (7.9)	0.46	0.04
LVEF <50%	101 (15.7)	117 (18.2)	0.23	0.07
Stroke volume index (mL/m2)	44.8±11.9	43.7±11.7	0.10	0.09
Stroke volume index ≤35 mL/m2	135 (21.2)	155 (24.3)	0.19	0.07
Eligibility for severe AS
High-gradient AS	333 (51.8)	343 (53.3)	0.58	0.03
Low-gradient AS	310 (48.2)	300 (46.7)
Low-gradient AS with reduced LVEF	65 (10.1)	75 (11.7)	0.37	0.05
Paradoxical low-flow low-gradient AS	60 (9.3)	64 (10.0)	0.71	0.02
Normal-flow low-gradient AS	184 (28.6)	158 (24.6)	0.10	0.09
LVMI (g/m2)	111.3±29.9	110.3±30.5	0.55	0.03
High LVMIA	349 (55.0)	336 (53.0)	0.46	0.04
Any combined valvular disease (moderate/severe)	156 (24.3)	175 (27.2)	0.23	0.07
Moderate or severe AR	55 (8.6)	65 (10.1)
Moderate or severe MS	12 (1.9)	26 (4.0)
Moderate or severe MR	72 (11.2)	82 (12.8)
Moderate or severe TR	69 (10.7)	75 (11.7)
TRPG ≥40 mmHg	79 (12.3)	83 (12.9)	0.74	0.02
Medications at index echocardiography
ACEi/ARB	504 (78.4)	479 (74.5)	0.10	0.09
β-blockers	314 (48.8)	327 (50.9)	0.47	0.04
Thiazides	53 (8.2)	40 (6.2)	0.16	0.08
Aspirin	202 (31.4)	177 (27.5)	0.13	0.09
Thienopyridine	88 (13.7)	100 (15.6)	0.34	0.05
Statins	327 (50.9)	317 (49.3)	0.58	0.03
Warfarin	65 (10.1)	67 (10.4)	0.85	0.01
DOAC	123 (19.1)	130 (20.2)	0.62	0.03
Treatment strategy
Initial AVR strategy	345 (53.7)	334 (51.9)	0.54	0.03
SAVR	118 (34.2)	100 (29.9)	0.23	0.09
TAVI	227 (65.8)	234 (70.1)
Conservative strategy	298 (46.3)	309 (48.1)	0.54	0.03

Categorical variables are presented as n (%). Continuous variables are presented as the mean±SD. Anemia was defined as serum hemoglobin <12.0 g/dL in women and <13.0 g/dL in men. ^AHigh left ventricular mass index (LVMI) was defined as LVMI >115 g/m² in men and >95 in women g/m². ACEi, angiotensin-converting enzyme inhibitor; AR, aortic regurgitation; ARB, angiotensin receptor blocker; AS, aortic stenosis; AVA, aortic valve area; AVR, aortic valve replacement; BMI, body mass index; BSA, body surface area; CCB, calcium channel blocker; DOAC, direct oral anticoagulant; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MR, mitral regurgitation; MS, mitral stenosis; NYHA, New York Heart Association; PG, pressure gradient; SAVR, surgical aortic valve replacement; SMD, standardized mean difference; TAVI, transcatheter aortic valve implantation; TR, tricuspid regurgitation; TRPG, tricuspid regurgitation pressure gradient; V_max, peak aortic jet velocity.

Clinical Outcomes

The median follow-up duration was 2.3 years (IQR 1.4–3.1 years). In the PS-matched cohort, the cumulative 3-year incidence of the primary outcome measure did not differ between the CCB and no CCB groups (38.3% vs. 38.7%, respectively [log-rank P=0.65]; HR 0.94 [95% CI 0.77–1.15; P=0.56]; Figure 2A; Table 3). In addition, there were no significant differences between the CCB and no CCB groups in the cumulative 3-year incidence of all-cause death (29.7% vs. 31.1%, respectively [log-rank P=0.08]; HR 0.80 [95% CI 0.64–1.02; P=0.07]) and hospitalization for heart failure (19.5% vs. 19.2%, respectively [log-rank P=0.57]; HR 1.05 [95% CI 0.79–1.40; P=0.72]; Figure 2B,C; Table 3). There was no significant difference in the risk of cardiovascular death, non-cardiovascular death, and aortic valve-related death between the CCB and no CCB groups, but the risk of sudden death was significantly lower in the CCB group (Table 3). The cumulative 3-year incidences of syncope and syncope or presyncope were very low, and did not differ between the CCB and no CCB groups (1.1% vs. 1.0%, respectively, for syncope [P=0.74]; 1.5% vs. 1.0%, respectively, for syncope/presyncope [P=0.75]; Table 3).

Figure 2.

Kaplan-Meier curves for (A) the primary outcome measure, (B) all-cause death, and (C) hospitalization for heart failure in the propensity score-matched cohort. The cumulative incidence was estimated using the Kaplan-Meier method, and differences were assessed using log-rank tests. CCB, calcium channel blocker.

Table 3.

Clinical Outcomes in the Propensity Score-Matched Cohort

	Cumulative incidence at 3 years		HR (95% CI)	P value
	CCB group (n=643)	No CCB group (n=643)
Primary outcome measureA	189 (38.3)	213 (38.7)	0.94 (0.77–1.15)	0.56
Secondary outcome measures
All-cause death	131 (29.7)	171 (31.1)	0.80 (0.64–1.02)	0.07
Cardiovascular death	66 (16.0)	92 (18.8)	0.73 (0.53–1.02)	0.06
Non-cardiovascular death	65 (16.4)	79 (15.2)	0.89 (0.64–1.24)	0.49
Aortic valve-related death	41 (9.8)	54 (11.4)	0.74 (0.49–1.13)	0.16
Sudden death	13 (4.2)	26 (5.2)	0.48 (0.24–0.96)	0.04
Hospitalization for heart failure	101 (19.5)	99 (19.2)	1.05 (0.79–1.40)	0.72
Stroke	28 (4.7)	30 (6.3)	1.06 (0.63–1.78)	0.83
Disabling stroke	21 (3.5)	19 (4.5)	1.31 (0.70–2.45)	0.39
Syncope	4 (1.1)	5 (1.0)	0.80 (0.21–3.00)	0.74
Syncope or presyncope	6 (1.5)	5 (1.0)	1.22 (0.37–4.04)	0.75

Unless indicated otherwise, data are given as n (%). ^AThe primary outcome measure was all-cause death or hospitalization for heart failure. The number of patients with an event was evaluated throughout the entire follow-up period, with the cumulative incidence estimated at 3 years. Syncope was defined as transient loss of consciousness due to cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous complete recovery.¹² Presyncope was defined as a state that resembles the prodrome of syncope, but which is not followed by loss of consciousness.¹² CCB, calcium channel blocker; CI, confidence interval; HR, hazard ratio.

As shown in Figure 3, the neutral risk of the CCB group relative to the no CCB group was consistent regardless of whether an initial AVR or conservative strategy was chosen and without significant interaction for the primary outcome measure (HR 1.10 [95% CI 0.80–1.51; P=0.55] and HR 0.86; [95% CI 0.66–1.12; P=0.26] for initial AVR and conservative strategy, respectively; P interaction=0.42), all-cause death (HR 1.03 [95% CI 0.71–1.49; P=0.90] and HR 0.70 [95% CI 0.51–0.95; P=0.02], respectively; P interaction=0.19), and hospitalization for heart failure (HR 1.33 [95% CI 0.82–2.14; P=0.25] and HR 0.94 [95% CI 0.66–1.35; P=0.74], respectively; P interaction=0.37). The neutral risk of the CCB group relative to the no CCB group was also consistent regardless of age or V_max for the primary outcome measure, all-cause death, and hospitalization for heart failure (Supplementary Figures 3,4). The results of the sensitivity analyses using the multivariable Cox proportional hazard models in the entire study population were fully consistent with analyses in the PS-matched cohort (Supplementary Table 2).

Figure 3.

Subgroup analyses stratified by the initial treatment strategies in the propensity score-matched cohort. The number of patients with an event was evaluated throughout the entire follow-up period, with the cumulative incidence estimated at 3 years. AVR, aortic valve replacement; CCB, calcium channel blockers; CI, confidence interval; HR, hazard ratio.

Characteristics of Patients With Syncope During Follow-up

In the entire study population, patients with syncope during follow-up more often had prior symptomatic stroke and hemodialysis than patients without syncope (Supplementary Table 3). Regarding initial treatment strategy, 80% of patients with syncope during follow-up were managed with a conservative strategy (Supplementary Table 3).

Discussion

The main findings of this study are as follows: (1) among patients with severe AS and hypertension receiving antihypertensive therapy, CCBs were prescribed to more than 70% of patients, being the most commonly prescribed antihypertensive agents; (2) clinical outcomes were comparable between groups receiving antihypertensive therapy with and without CCBs, and this was consistent regardless of the choice of initial AVR or a conservative strategy; and (3) the incidence of syncope or presyncope was extremely low in patients with severe AS and hypertension receiving antihypertensive therapy, regardless of CCB prescription.

Hypertension has been reported as a risk factor for the progression of AS, which may be one reason for the high prevalence of patients with both AS and hypertension.^{1–3,15–17} Because hypertension adds to total pressure overload on the LV combined with aortic valve obstruction, hypertension is associated with abnormal LV structure, including LV hypertrophy, LV systolic dysfunction, and reduced stroke volume, which could ultimately lead to a poor prognosis.^1,4,5 Therefore, current US and European guidelines state that hypertension should be treated in patients with AS.^6–10 Small RCTs and observational studies have shown a clinical benefit of antihypertensive therapy in patients with AS and hypertension, although there have been no large scale RCTs demonstrating the efficacy of antihypertensive therapy in patients with AS and hypertension.^18–23

The optimal antihypertensive therapy drug class in patients with AS and hypertension remains unknown. The European consensus document recommends ACEi/ARB as first-line therapy, and the addition of β-blockers, if needed, based on positive results of very small RCTs (sample size <100) and observational studies in patients with AS and hypertension.^1,18–23 Because of the scarcity of studies evaluating vasodilators like CCBs and clinical outcomes, CCBs are not considered as first-line therapy in the consensus document.^1,2 There is a concern that vasodilators like CCBs or nitrates could reduce the stroke volume in patients with AS due to aortic valve obstruction. However, hemodynamic studies using vasodilators such as nitroprusside or phosphodiesterase type 5 inhibitors in patients with severe AS demonstrated that the vasodilators reduced LV filling pressures and pulmonary artery pressures and increased stroke volume.^24–26 Therefore, the concept that vasodilators may have adverse effects in patients with severe AS and hypertension is not adequately supported by the data. In contrast to the recommendations in the consensus document,¹ in the present real-world study, CCBs were the most commonly prescribed antihypertensive therapy in patients with severe AS, suggesting that there is no reluctance among most physicians to prescribe CCBs to patients with severe AS and hypertension in real-world clinical practice. It was reassuring that, in the present study, the clinical outcomes of antihypertensive therapy were comparable between the CCB and no CCB groups, with the latter primarily consisting of the use of ACEi, ARB, and β-blockers. When treating hypertension in patients with severe AS, the most important thing may be to achieve optimal BP control rather than the choice of class of antihypertensive therapy, with the results of the present study indicating that we may not need to refrain from using CCBs for the treatment of hypertension in patients with severe AS. CCBs may be an important option, especially in patients with severe AS who need to take multiple antihypertensive drugs. Conversely, CCB prescriptions should be avoided in patients with severe AS and reduced LVEF, because CCBs are not recommended in patients with reduced LVEF in the general hypertensive population.¹⁰

Concerns remain about hypotension caused by antihypertensive therapy in patients with AS and hypertension in real-world clinical practice, especially in elderly patients. However, in this study, the incidence of syncope or presyncope was extremely low in patients with severe AS and hypertension receiving antihypertensive therapy, regardless of CCB prescription, reflecting real-world patients with severe AS and hypertension (mean age 82 years). The European Society of Hypertension guidelines state that the BP thresholds and targets, as well as the drug treatment strategies, should be the same in patients with AS as in the general hypertensive population.¹⁰ Previous studies suggested that LV systolic dysfunction and congestive heart failure were associated with symptomatic hypotension in patients with AS receiving antihypertensive therapy.^18,27 In the present study, the vast majority of severe AS patients who experienced syncope were treated with a conservative strategy, and the prevalence of prior symptomatic stroke and hemodialysis was higher among patients with than without syncope. In these AS patients at high risk of symptomatic hypotension and syncope, hypertension should be treated more cautiously, such as starting with a low dose, gradual titration, and appropriate monitoring.

Study Limitations

This study has several important limitations. First, and most importantly, the present study was not an RCT. Despite PS matching and multivariable analyses, selection bias and residual confounding may not have been entirely eliminated. Second, we did not have data on the actual indication for prescriptions of CCB, ACEi/ARB, β-blockers, and thiazides. These drugs may be prescribed due to heart failure, arrhythmia, and ischemic heart disease rather than hypertension. Differences in the prevalence of prior myocardial infarction, heart failure, atrial fibrillation or flutter, and LV systolic dysfunction between the groups may represent different indications for antihypertensive therapy. Third, we did not collect data on BP and changes in medications during the follow-up period, or on non-compliance with antihypertensive therapy. Therefore, we could not consider the effects of non-compliance or discontinuation of antihypertensive therapy and analyze the data based on an intention-to-treat principle. However, considering the very low incidence of syncope or presyncope during follow-up, we believe that the incidence of discontinuation of antihypertensive therapy may not have been high, and the effects of discontinuation may not have been large in this study. Fourth, we did not collect data on the types of CCB (dihydropyridines or non-dihydropyridines) or dosage.

Conclusions

In conclusion, among patients with severe AS and hypertension, CCBs were the most commonly prescribed antihypertensive agents, and clinical outcomes were comparable between antihypertensive therapy with CCBs and that without CCBs. Syncope was rarely seen in patients with severe AS and hypertension receiving antihypertensive therapy regardless of CCB prescription.

Acknowledgments

The authors extend their appreciation to the study investigators for their efforts in enrolling patients and collecting data.

Sources of Funding

This work was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).

Disclosures

T.M. reports lecturer fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Pfizer, Tsumura, and UCB; manuscript fees from Pfizer; and being on the advisory board for GlaxoSmithKline, Novartis, and Teijin. T. Kimura reports being on the advisory board for Abbott Vascular; grants from Edwards Lifescience, Daiichi Sankyo, Takeda Pharmaceutical, Bayer, Otsuka Pharmaceutical, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Kowa, Abiomed, Japan Academic Research Forum, NIPRO, W. L. Gore & Associates G.K., RPM Co., Ltd., CSL Behring, Pfizer R&D Japan G.K., and EP-CRSU Co., Ltd; honoraria from MSD, Eisai, Edwards Lifescience, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Pharmaceuticals and Medical Devices Agency, Bristol-Myers Squibb, Boston Scientific, Toray, Astellas Amgen Biopharma, AstraZeneca, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma, HeartFlow Japan G.K., and CROSSCO Co. K. Ono and K. Minatoya are members of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

The present study was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (Reference no. R1501).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0771

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