Authors: Hongtao Tie, Zhenhan Li, Henryk Welp, Avirup Guha, César Caraballo, Heinz Deschka, Rui Shi, Xiaoqing Zheng, Sven Martens, Jürgen Sindermann, Dan Chen, Qingchen Wu, Sabrina Martens
Categories: Original Articles, Adverse events, Calcium channel blocker, LVAD, Survival, Original Article
Source: ESC Heart Failure
Doi: 10.1002/ehf2.14576
Current guidelines suggest calcium channel blockers (CCBs) as the second or third option for blood pressure management in patients with left ventricular assist device (LVAD). However, the clinical outcomes of patients with LVAD who receive CCBs remain unclear. Our study aims to analyse the association of CCBs with clinical outcomes in patients after LVAD implantation.
This is a retrospective analysis based on the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2006 to 2017, and adult patients who were alive with LVAD and CCB treatment information at 6 months after implantation were included. Among 10 717 patients, 1369 received CCBs 6 months after implantation, and there was an increasing trend of CCB use after LVAD. Patients receiving CCB therapy at 6 months had a similar 5 year survival rate to those not receiving CCB [49.6%, 95% confidence interval (CI): 47.5–51.7% vs. 51.1%, 95% CI: 45.3–56.7%]. In both Cox and competing risk regressions after adjusting for confounding factors, CCB treatment at 6 months after implantation was not associated with long‐term mortality [hazard ratio (HR): 1.03, 95% CI: 0.91–1.17, P = 0.624 and subdistribution HR (SHR): 1.07, 95% CI: 0.95–1.22, P = 0.260]. Consistently, in time‐varying models, CCB treatment was not linked to long‐term mortality (HR: 0.97, 95% CI: 0.87–1.09, P = 0.682 and SHR: 1.05, 95% CI: 0.94–1.18, P = 0.359). This null association remained in subgroup analysis according to device strategy and propensity‐matching analyses. Neurological dysfunction, stroke, bleeding, rehospitalization, and renal dysfunction were more likely to occur among those with CCB when compared with those without CCB treatment.
In patients with LVAD, CCB therapy fails to show benefits in long‐term survival and is associated with increased incidences of neurological dysfunction, bleeding, renal dysfunction, and rehospitalization.
Keywords: Calcium channel blocker, LVAD, Survival, Adverse events
The limitations of heart transplantation and contemporaneous improvements of devices make left ventricular assist devices (LVADs) an excellent alternative for end‐stage heart failure therapy. In the past decade, there was a dramatic increase in the number of LVAD implantations, with more than 25 000 adult patients receiving LVADs in the United States, and the number is continuously increasing to approximately 5000 per year worldwide annually. ^1^ , ^2^ However, except for anticoagulation, optimal pharmacotherapy strategies in patients after LVAD implantation remain unclear and standardized treatment needs to be established urgently. ^3^
In patients without heart failure, calcium channel blockers (CCBs) are effective in the treatment of hypertension, stable angina, and supraventricular arrhythmias and showed a preventive effect on associated cardiovascular events in monotherapy and combination use. ^4^ However, in patients with heart failure with reduced ejection fraction (HFrEF), the European Society of Cardiology and American College of Cardiology Foundation/American Heart Association guidelines recommend that first‐generation CCBs should generally be avoided as they may possess a negative inotropic effect and increase sympathetic tone. ^5^ , ^6^ With the mechanical unloading of the left ventricle by LVAD, the myocardial depression effect of CCBs might be mitigated and trivial. Current guidelines suggest that CCBs could be used as the second or third option for blood pressure management in patients with heart failure. ^7^ However, little is known about the association between CCB treatment and clinical outcomes in patients with LVAD. In this study, we aim to determine the effect of CCBs on clinical outcomes among patients with continuous‐flow LVAD using the data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry.
The ethics committee of the Westfalen‐Lippe Medical Association and the Westphalian Wilhelms University Muenster approved this study. We acquired the data from the INTERMACS registry, a prospective database that includes adults who received mechanical circulatory support devices due to end‐stage heart failure from 2006 to 2017. The data used in this study were requested from the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung, and Blood Institute (https://biolincc.nhlbi.nih.gov/).
We included adult (≥18 years old) patients alive and with the device in place 6 months after their initial device implantation. We determined the 6 month survival with devices in place conditional because left ventricle function recovery, medication therapy, and clinical status stabilize 6 months after LVAD implant. ^8^ Supporting Information, Figure
S1 illustrates the detailed patient selection process.
Baseline variables and outcomes were defined according to standard INTERMACS definitions. ^9^ The primary outcome was long‐term mortality from 6 months to 5 years after LVAD implantation. The secondary outcomes were adverse events and quality of life (QoL). Adverse events, including neurological dysfunction, stroke, bleeding, rehospitalization, renal dysfunction, infection, cardiac arrhythmia, psychiatric episode, and right heart failure, were analysed using time to first event, and QoL was indicated by the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.
Continuous variables were expressed as mean with standard deviation, and differences between the groups were compared by independent t‐test or analysis of variance when appropriate. Categorical variables were described as counts with percentages, and χ ^2^ or Fisher's exact test were used to check the differences when appropriate.
Cox proportional hazards models were employed to assess the effect of CCB medication 6 months after implant on survival and the time to first adverse events. In this analysis, CCB therapy was considered as a time‐constant variable. Because medication therapy changed over time, the CCB medication group was treated as a time‐varying variable to avoid immortal time bias. ^10^ Patients' survival data and CCB medication therapy at each follow‐up time were converted to a counting process form in R software (Version 3.4.0) with a survival package, and a time‐varying Cox proportional hazards model was constructed.
In addition, multivariable Cox regressions were also performed, adjusted for age, gender, body mass index (BMI), modified Charlson comorbidity index, albumin, total bilirubin, blood urea nitrogen, current implantable cardioverter‐defibrillator, INTERMACS Level 1 or 2, dialysis, history of cardiac surgery, concomitant cardiac surgery, year of implant, institutional annual implant volume, and implant indication. Modified Charlson comorbidity index was estimated according to a previous study, ^9^ and the individual BMI was calculated. Institutional annual implant volume was the average between 2014 and 2016. The natural logarithm of total bilirubin and blood urea nitrogen was used to reduce skewness. The missing data for these adjusted variables were replaced by means, with the highest missing rate of albumin (16%). The Schoenfeld residual test was performed, and all terms entered in the multivariable Cox analysis met the proportional hazard assumption, or the extended Cox regressions model was used.
Due to the competing risk among primary outcomes of mortality, heart transplantation, and explant, the cumulative incidence functions and competing risk model according to the Fine–Gray method were also used to assess the role of CCB medication on these clinical outcomes. ^11^ For the survival analysis, endpoints of heart transplantation and explant due to recovery were considered competing events. For adverse events, competing risk factors were mortality, heart transplantation, and explant due to recovery. Multivariable competing risk regression analysis was also performed. For adjusted factors violating the proportional hazards assumption, time‐varying coefficients for these variables were applied in the multivariable competing risk regression.
Propensity‐matching analysis was used to reduce potential residual confounding in multivariable analysis, with covariates from the adjusted factors. We performed a 1 propensity score matching without replacement by the nearest neighbour method, and the matching effectiveness was evaluated by propensity score distribution and per cent bias reduction after matching.
KCCQ scores at each follow‐up time point were compared between the two groups using an independent t‐test. All statistical analyses were performed with Stata/MP 17.0 (StataCorp), and two‐tailed P values < 0.05 were considered significant. The estimated effect was reported as hazard ratios (HRs) and subdistribution HRs (SHRs) with 95% confidence intervals (CIs).
A total of 10 717 patients from INTERMACS who received LVAD between 2006 and 2017 and were still alive with the device 6 months after implant were included. Baseline characteristics at 6 months after implantation are summarized in Table
1 . The median age was 57.1 ± 13.0 years, 79.5% were men, 66.1% were White, and 52.6% had non‐ischaemic heart disease. The indications were bridge to transplantation (BTT) in 5765 (53.8%), bridge to recovery in 56 (0.52%), and destination therapy (DT) in 4862 (45.4%) cases. Regarding comorbidities, 5.26% of the patients had severe diabetes, 10.6% atrial arrhythmia, 2.7% peripheral vascular disease, 5.5% pulmonary disease, 10.8% pulmonary hypertension, and 12.5% chronic kidney disease.
When compared with patients without CCB use (n = 9348, 87.2%), those with CCB treatment (n = 1369, 12.8%) were more likely to be African American and had a higher prevalence of atrial arrhythmia, chronic kidney disease, dialysis, and New York Heart Association Class III–IV. The prevalence of previous cardiac surgery was lower in patients receiving CCB, and patients without CCB use tended to have a higher proportion of centrifugal LVAD. Regarding medication therapy, there were significant differences in using hydralazine, digoxin, phosphodiesterase inhibitors, warfarin, angiotensin‐converting enzyme (ACE) inhibitors, and aldosterone antagonists. The other variables were comparable between the two groups.
Laboratory results, haemodynamics, and echocardiography at 6 months after LVAD implantation are shown in Supporting Information, Table
S1 . Patients receiving CCB therapy had higher creatine, blood urea nitrogen, pre‐albumin, and platelets than patients without CCB use. Compared with patients without CCB therapy, systolic blood pressure level was higher in those treated with CCB. There was a lower incidence of aortic regurgitation, and the left ventricle tended to be smaller in patients with CCB therapy. As shown in Supporting Information, Table
S2 , patients with CCB treatment had a higher systolic blood pressure and Doppler opening pressure during follow‐up than patients without CCB treatment.
The proportion of patients receiving CCB therapy increased from 12.4% at 6 months after implant to 18.7% at 18 months and reached a plateau of ~20% thereafter, as shown in Figure
1 . Besides, from 2011 to 2017, there was an increasing trend of CCB treatment at different follow‐up time points after LVAD implantation.
Figure 1 Calcium channel blocker (CCB) therapy after left ventricular assist device (LVAD) implant according to follow‐up time and year of implantation.
Kaplan–Meier survival curves between CCB and no‐CCB groups at 6 months after implantation are shown in Supporting Information, Figure
S2 . The unadjusted 5 year survival estimate was 49.6% (95% CI: 47.5–51.7%) for the CCB group and 51.1% (95% CI: 45.3–56.7%) for the no‐CCB group at 6 months after implant. No difference was identified from univariable (HR: 1.02, 95% CI: 0.98–1.16, P = 0.704) or multivariable Cox regressions (HR: 1.03, 95% CI: 0.91–1.17, P = 0.624). The lack of association between CCB and mortality remained still when stratified according to device strategy (BTT and DT) and when CCB medication was analysed as a time‐varying variable (Figure 2 ).
Figure 2 Kaplan–Meier survival curve of 5 year mortality according to time‐varying calcium channel blocker (CCB) therapy for all patients (A), patients with bridge to transplantation (BTT) as device strategy (B), and patients with destination therapy (DT) as device strategy (C), and forest plot of hazard ratios (HRs) for time‐varying CCB therapy on mortality from Cox regression model (D). CI, confidence interval; LVAD, left ventricular assist device.
In competing risk models, treating heart transplantation and explant due to recovery as competing events, adjusted SHRs using CCB therapy as time‐constant (SHR: 1.07, 95% CI: 0.95–1.22, P = 0.260; Supporting Information, Figure
S3 ) and time‐varying variable (SHR: 1.05, 95% CI: 0.94–1.18, P = 0.359; Supporting Information, Figure
S4 ) showed no effect of CCB therapy on survival among patients after LVAD.
After propensity matching, all covariables became comparable between the two groups (Supporting Information, Table
S3 ). Both time‐varying Cox (HR: 0.96, 95% CI: 0.81–1.13, P = 0.595) and competing risk regressions (SHR: 0.93, 95% CI: 0.79–1.11, P = 0.452) consistently verified that CCB treatment was not associated with higher mortality in patients with LVAD.
Cumulative incidence functions and competing risk analysis were employed to investigate the association between CCB therapy and time to first adverse events (ranging from 6 months to 5 years). As shown in Figure
3 , when treating CCB therapy as a time‐varying variable, cumulative incidences of neurological dysfunction (29.5% vs. 21.0%), stroke (21.6% vs. 14.5%), bleeding (43.4% vs. 35.1%), rehospitalization (94.5% vs. 90.7%), and renal dysfunction (13.6% vs. 7.6%) at 5 years were significantly higher in the CCB group. Both univariate and multivariable competing risk regressions revealed that CCB therapy was associated with significantly increased incidences of these adverse events. No differences in infection, cardiac arrhythmia, psychiatric episodes, and right heart failure between the CCB and non‐CCB groups were identified when treating CCB therapy as a time‐varying variable (Supporting Information, Figure
S5 ). The results held true when analysed according to CCB therapy at 6 months after LVAD implant (Supporting Information, Figures
S6 and S7 ).
Figure 3 Cumulative incidence functions of time‐varying calcium channel blocker (CCB) therapy on cumulative incidences of neurological dysfunction (A), stroke (B), bleeding (C), rehospitalization (D), renal dysfunction (E), and forest plot of subdistribution hazard ratios (SHRs) from competing risk regression model (F). CI, confidence interval; LVAD, left ventricular assist device.
Figure
4 presents post‐implant KCCQ scores 6–24 months after implantation. CCB therapy failed to show differences in KCCQ scores at 6 (66.8 ± 20.1 vs. 67.5 ± 20.0, P = 0.276), 12 (67.4 ± 20.0 vs. 66.9 ± 20.6, P = 0.558), 18 (66.0 ± 20.8 vs. 66.3 ± 20.8, P = 0.378), or 24 months after LVAD implant (65.1 ± 20.8 vs. 66.1 ± 20.6, P = 0.151).
Figure 4 Quality of life indicated by Kansas City Cardiomyopathy Questionnaire (KCCQ) scores over time between calcium channel blocker (CCB) and no‐CCB groups. LVAD, left ventricular assist device.
In the current study, including 10 717 participants who survived more than 6 months, we investigated the effect of CCB therapy on clinical outcomes in patients after LVAD implantation. Our study has four important findings. First, the proportion of patients receiving CCB therapy increased after LVAD implantation. Besides, from 2011 to 2017, there was also an increasing trend of CCB therapy at different follow‐up time points. Second, CCB therapy was not associated with improved survival. Third, CCB treatment was associated with significantly increased neurological dysfunction, stroke, bleeding, rehospitalization, and renal dysfunction. Fourth, there was no difference in QoL between patients receiving CCB and those not receiving CCB. These findings demonstrated that CCB therapy failed to show benefits in long‐term survival and was associated with increased incidences of adverse events.
Current guidelines recommend that amlodipine and felodipine should be considered to relieve angina in patients with heart failure with preserved ejection fraction (HFpEF) and coronary artery disease and may be supposed to lower blood pressure in patients with HFrEF without fluid overload. ^5^ However, a real‐world analysis showed that CCBs were the most frequently prescribed antihypertensive drug in hypertensive patients with heart failure, with a proportion of 55.0–56.5%. Besides, CCBs had exceeded angiotensin II receptor blockers (ARBs) as the most prescribed first‐line antihypertensive drugs in these patients, with 26.0–26.8% after 2013. ^12^ Even in patients with HFrEF, it was reported that 4.7–7.3% were discharged on contraindicated CCB. ^13^ , ^14^ Our study found that the proportion of patients with CCB gradually increased after LVAD and reached a plateau of ~20% after 18 months. Besides, there was also an increase in CCB treatment at different follow‐up time points from 2011 to 2017. The high proportion of patients receiving CCBs and its increasing trend highlights the great need to elucidate the role of CCB in managing patients with LVAD.
Owing to the higher selectivity for calcium channels in vascular smooth muscle cells, the second‐generation dihydropyridine CCBs are safe in patients with heart failure. ^15^ A 12 year follow‐up prospective cohort study with 438 participants found that CCB treatment was associated with significant decreases in mortality and major cardiovascular events in HFpEF, ^16^ while the beneficial effect of CCBs was not identified in older HFpEF patients by a large‐scale study. ^17^ Besides, several randomized controlled trials showed no benefit of dihydropyridine in patients with HFrEF and HFpEF. ^18^ , ^19^ Even one study found that CCB conferred an increased risk of readmission in patients with HFrEF. ^13^ Currently, no definite evidence supports the prognostic benefit of CCBs in patients with heart failure. Consistently, our current study found that CCB treatment failed to benefit patients after LVAD.
Hypertension is common among LVAD patients and causes an increased afterload for LVAD patients, leading to reduced LVAD flow and less left ventricular unloading. Besides, it has been proven to be an established risk factor for adverse events. ^20^ Traditional heart failure treatment with neurohormonal blockade (NHB), including ACE inhibitors or ARBs, beta‐blockers, and mineralocorticoid receptor antagonists and diuretics, is recommended to control the blood pressure by current guidelines in selected LVAD patients. ^7^ , ^8^ , ^21^ NHB therapy is correlated with improved survival and QoL in patients with long‐term LVAD support. ^9^ CCBs, acting as a first‐line blood pressure‐lowering drug, were not associated with improved survival in patients with LVAD. The following facts may explain this finding. First, CCBs were proposed as second‐ or third‐line medication for blood pressure management. Patients with CCB treatment had poorly controlled hypertension under the first‐line antihypertensive therapy, which can be indicated by the higher systolic blood pressure and Doppler opening pressure at the baseline, a higher proportion of hydralazine use at the baseline, and the higher systolic blood pressure and Doppler opening pressure during follow‐up in our study. Second, ACE inhibitors or aldosterone antagonists have been verified to be effective in improving outcomes in patients with heart failure and are also recommended by the guideline in LVAD patients. ^7^ , ^8^ , ^21^ We found significantly fewer patients with ACE inhibitor or aldosterone antagonist treatment in the CCB group, indicating that patients under CCB therapy may have some contraindications for ACE inhibitor and aldosterone antagonist use. Third, though no reliable markers for renal function, patients in the CCB group tend to have poor kidney function at baseline, indicated by a higher incidence of chronic kidney disease, dialysis, increased blood urea nitrogen, and increased creatinine. As ACE inhibitors and aldosterone antagonists are contraindicated to poor kidney function, ^6^ our second suppose was also supported by the incomparable kidney function at baseline. Therefore, though multivariable and time‐varying methods were employed, the real effect of CCB on long‐term mortality may be driven by these unbalanced variables, and this finding should be treated with caution.
Besides, we found that patients with CCB therapy had increased risks of neurological dysfunction, stroke, bleeding, rehospitalization, and renal dysfunction. Previous studies reported that CCBs were associated with an elevated risk of bleeding in patients with hypertension. ^22^ , ^23^ Besides, in patients with anticoagulant therapy, the use of CCBs was associated with increased risks of major bleeding and intracranial haemorrhage. ^24^ , ^25^ Patients with LVAD often take anticoagulants (warfarin and/or other potential anti‐platelet drugs), and LVAD itself can cause angiodysplasia, abnormal angiogenesis, impaired platelet aggregation, and pathological von Willebrand factor degradation, resulting in an increased bleeding risk. ^26^ , ^27^ Therefore, patients with LVAD are at high risk for bleeding, and CCB treatment further exacerbates the bleeding tendency. Consistent with our findings, evidence supports that CCB therapy is associated with worsening renal function in patients with heart failure. ^28^ , ^29^ However, the poor kidney function in patients with CCB treatment at baseline might confound the results. In the treatment of hypertension, CCBs appear to have beneficial effects on stroke prevention in comparison with beta‐blockers and ACE inhibitors. ^30^ However, when combined with ACE inhibitors for hypertension treatment, CCBs were associated with increased stroke and heart failure risks compared with diuretics. ^31^ In LVAD patients, CCBs were usually used as combination therapy because they were the second or third option for blood pressure control. The risk of stroke in patients taking CCBs could be due to the combination treatment. It should be noted that hypertension was poorly controlled in patients with CCBs at baseline, and higher blood pressure caused increased bleeding, stroke, and mortality. ^20^ This evidence suggests that CCBs are correlated with increased adverse events, but this correlation should be interpreted cautiously.
Limitations exist in the current study. First, this is a retrospective study using registry data, and some variables are not comparable between the two groups. Though the propensity‐score‐matching method, multivariable Cox regression, and competing regression were used, the real effect of CCBs may still be confounded. Second, considering CCB treatment varying during follow‐up, time‐varying analysis was performed in our study, while the dosage, compliance, and reason for initiation or discontinuation of CCBs remained unclear and unexplored. Third, the type of CCB on the effect of outcomes in LVAD patients should be analysed as the second‐generation dihydropyridine CCB with higher selectivity for calcium channels in vascular smooth muscle cells has been confirmed to be safe. While the type of CCB was unclear in the INTERMACS registry, this important issue remains unexplored. Fourth, with the development and dominance of newer LVADs, the LVAD varied from 2006 to 2017 and the analysed LVAD in our study may not represent the contemporary population with LVAD support. The association of the device type with the outcomes in patients with CCB needs further investigation. Based on the above, our findings should be interpreted carefully because of the limitation of the observation study.
The current study suggests an increasing trend of CCB use in patients after LVAD, while CCB therapy was not associated with improved survival and QoL in patients after LVAD. Some findings indicate that CCB usage may increase the risk of neurological dysfunction, bleeding, renal dysfunction, and rehospitalization. Considering the limitations of our study, there is a need for randomized clinical studies to investigate this.
The authors have no conflicts of interest to declare.
This work was supported by the National Natural Science Foundation of China (No. 81700602), the First‐Class Discipline Construction Project of First Clinical College, Chongqing Medical University (No. CYYY‐BSHPYXM‐2022‐08), and the Natural Science Foundation of Chongqing, China (No. CSTB2022NSCQ‐MSX0840), the CQMU Program for Youth Innovation in Future Medicine (W0153), the CQMU Young Outstanding Scientific and Technological Talents Program (ZYRC2022‐04), and the Youth Project of Science and Technology Research Program of Chongqing Education Commission of China (KJQN202300482).
This article was analysed using the data from INTERMACS obtained from the National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center.
Open Access funding enabled and organized by Projekt DEAL.
Tie, H. , Li, Z. , Welp, H. , Guha, A. , Caraballo, C. , Deschka, H. , Shi, R. , Zheng, X. , Martens, S. , Sindermann, J. , Chen, D. , Wu, Q. , and Martens, S. (2024) Calcium channel blockers and clinical outcomes in patients with continuous‐flow left ventricular assist devices. ESC Heart Failure, 271–281. 10.1002/ehf2.14576.