Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients. Freisinger E, Gerß J, Makowski L, Marschall U, Reinecke H, Baumgartner H, Koeppe J, Diller GP.Eur Heart J. 2020 Nov 14;41(43):4168-4177. doi: 10.1093/eurheartj/ehaa844.PMID: 33184662 Take Home Points Observational dataset of 44,000 ACHD patients between 2005-2018. 5,465 ACHD patients on oral anticoagulant treatment were within the dataset. ACHD patients identified from a German health insurance dataset which covered 9 million insured persons (Total population Germany 83 million). It is unclear the proportion of patients in this dataset under specialist ACHD care – it is possible, many were not. Evaluation of the use of DOAC agents compared to vitamin K antagonists. Use of oral anticoagulants (NOAD/DOAC and vitamin K antagonists) doubled from 6% to 12%. In this German dataset, DOACs accounted for 45% of prescribed anticoagulants by 2018 - most frequently prescribed agents were rivaroxaban and apixaban (80% of dataset). ACHD patients on DOACs had higher thromboembolic (3.8% vs 2.8%); MACE (7.8% vs 6%); bleeding rates (11.7% vs 9%) and all-cause mortality (4% vs 2.8%) after 1 year of therapy compared to vitamin K antagonists. After adjustment for patient characteristics, DOACs remained associated with a greater risk of MACE (HR 1.22; 95% CI 1.09-1.36), all-cause mortality (HR 1.43; 95% CI 1.24-1.65; both P<0.001) and bleeding (HR 1.16; 95% CI 1.04-1.29; p=0.007). Commentary from Dr. Damien Cullington (Liverpool, United Kingdom), section editor of ACHD Journal Watch: Novel oral anticoagulant agents (NOACs) have been approved for use for approximately a decade which means they are not so novel and more commonly referred to direct oral anticoagulant agents (DOACs). DOACs are a revolution in anticoagulant management. Take once or twice a day plus no irritating visits to the INR clinic, plus avoidance of the rollercoaster of INRs and shifting warfarin dose means there is all round delight with the therapeutic simplicity. Not all patients welcome DOACs with open arms. Some patients who have been treated with warfarin for long periods of time are skeptical and the lack of ‘knowing’ how anticoagulated they are with a DOAC causes concern and so often prefer to stay on warfarin (or other vitamin K antagonists), feeling more confident in its reliability (and predictability). Naturally, DOACs are not to be used in patients with mechanical valves. Following the introduction of most medicines, comes potential indication creep. DOACs were and are often prescribed outside the limits of their original licensing indication. This is only natural. This is a part of a more generic therapeutics issue in the world of ACHD where vanishingly few large randomised controlled trials of drug therapy exist and essentially most medical therapy indication is logically extrapolated from ‘acquired’ cardiology datasets. Rightly pointed out by the authors of this paper, “medical adherence, reach of effective doses or INRs, as well as potential pharmacological interactions in a real-world scenario may relevantly differ from controlled study settings.” This large observational ACHD dataset (n=44, 097) by Freisinger et al. makes one reflect about our prescribing habits with respect to choosing DOACs instead of vitamin K antagonists in ACHD patients. More specifically, using DOACs in an ‘off license’ fashion and in ACHD patient groups who have not been fully evaluated in randomised clinical trials. Figure 1 shows growth of DOAC use in this dataset between 2005-2018. Figure 1. Temporal growth of DOAC use in ACHD patients within a large German insurance dataset. The characteristics of the dataset are shown in Table 1. The total dataset comprised 44,097 ACHD patients. Of the total cohort, 12% (n=5465) were on anticoagulant treatment in 2018. As one would expect, the vast majority of patients (93%) had ‘simple’ or ‘moderate’ ACHD lesions. Increasing complexity of ACHD lesion was associated with a higher likelihood of being treated with an anticoagulant – 9% in simple lesions; 11% in moderate lesions and 14% in complex lesions (p <0.001). By 2018, the number of patients prescribed a DOAC in each of the complexity groups was similar. Patients with mechanical heart valves were excluded from longitudinal analysis. Median follow up time from first prescription of VKA was 90 months and 39 months for DOAC. The commonest reason for anticoagulation was atrial arrhythmias – two thirds of the group. Results (Table 2) The primary outcome data relating to bleeding, thromboembolic events and MACE are shown in Table 2. After adjustment for patients’ characteristics, there was increased bleeding risk for DOACs vs VKAs in follow up – HR 1.16; 95% CI 1.04-1.29; p=0.007. Of note, however, it is unclear the efficacy of anticoagulation in patients prescribed a VKA i.e. how much time is in range. One would expect lower rates of bleeding if anticoagulation were sub-therapeutic compared to DOACs where anticoagulation is ‘complete’. The adjusted risk of major bleeding or thromboembolism did not differ between treatment groups. MACE (HR 1.23; 95% CI 1.10-1.37; p<0.001) and all-cause mortality (HR 1.43; 95% CI 1.24-1.65; p<0.001) were significantly higher in ACHD patients prescribed a DOAC vs VKA. Univariable Cox regression analysis is shown in Figure 2. The authors comment that patients with chronic kidney or liver disease were particularly prone to complications. No interaction was seen between complexity of ACHD and risk posed by anticoagulation – complications were independent to anatomical lesion. Figure 2 Limitations This is a sizable dataset but it is observational, so caution is needed to draw absolute conclusions compared to RCTs. However, in the absence of any large RCTs comparing DOACs to VKA in patients with ACHD, the ‘signal’ from the results should be reflected upon. There is a significant amount of extra data in supplementary material which the reader is advised to scrutinise alongside the paper. Patients within this analysis are not specifically followed up in an ACHD specialist centre – the authors comment that up to a third of ACHD patients in Germany are not followed up in centres specialising in ACHD. This may well have a significant bearing on outcomes since it has been shown that care of ACHD patients in non-specialist centres is associated with worse outcomes. Other co-variates are missing from the analysis, such as ventricular dysfunction. Conclusions This large observational dataset has shown that after adjustment for patients’ characteristics, the HR for MACE (acute MI; ischaemic stroke; VF; resuscitation or death) was 1.2 and the HR=1.4 for all-cause death. Given this, as I am sure we all do, the results should be reflected upon and considered when prescribing DOACs to ACHD patients, particularly in the absence of clear RCT evidence. As I write my last sentence I feel the need to pull out an all too frequent trope which I state in all things ACHD, particularly with relation to medical treatment - randomised controlled data is needed to ensure results are not by chance and reflective of usual guideline based care of ACHD patients in specialist centres.
Assessment of hemodynamic responses to exercise in aortic coarctation using MRI-ergometry in combination with computational fluid dynamics
Assessment of hemodynamic responses to exercise in aortic coarctation using MRI-ergometry in combination with computational fluid dynamics. Schubert C, Brüning J, Goubergrits L, Hennemuth A, Berger F, Kühne T, Kelm M.Sci Rep. 2020 Nov 3;10(1):18894. doi: 10.1038/s41598-020-75689-z.PMID: 33144605 Free PMC article. Take Home Points: MRI ergometry in combination with Computational Flow Dynamics (CFD) can be used to noninvasively assess trans-stenotic pressure gradients, aortic flow patterns and stroke volume in patients with aortic coarctation at rest and during physical exercise. Therefore, no simulation of exercise using adrenergic drugs is necessary. This information has promising implications for clinical application and further research on the pathophysiology of aortic coarctation. Commentary from Dr. Soha Romeih (Aswan, Egypt), section editor of ACHD Journal Watch: Introduction For aortic coarctation, in the current clinical decision-making process, pressure gradients across the aortic narrowing is one of the decisive factors for potential re-intervention. As pressure gradients increase during exercise due to increased cardiac output, patients with gradients below the threshold for intervention at rest may develop pathologically high gradients during exercise. In the case of a borderline indication for surgical or catheter-based treatment, stress tests can help to unmask the hemodynamic relevance of the stenosis. Commonly used non-invasive methods for determining pressure gradients at rest or during physical exercise (e.g. echocardiography, cuff measurements) are often inaccurate. Alternatively, adrenergic drug infusions can be used during cardiac catheterization, simulating physical exercise, while measuring peak-to-peak gradients. However, the hemodynamic response during pharmacological stress is far from representing responses to actual physical exercise. The combination of MRI-ergometry and computational fluid dynamics (CFD) could be an approach to quantitatively assess the hemodynamic response to physical exercise. Combining these two methods, would allow an accurate and non-invasive assessment of pressure gradients, aortic and left ventricular hemodynamics at rest and during physical exercise, without the need for adrenergic drugs to simulate exercise. Patients and Methods: This is a prospective study in patients with aortic coarctation, who underwent cardiac MRI due to elevated Doppler gradients or follow-up after an intervention, between November 2018 and September 2019. Study design: Figure 1. (Upper panel) Visual illustration of the study design. Cardiac MRI of 20 participants with aortic coarctation was acquired during rest and moderate exercise. An absolute increase in heart rate of 50 bpm was targeted during exercise. Using the MRI images, the participant-specific aortic geometry was reconstructed Using computational fluid dynamics, the transstenotic pressure gradient was calculated during rest and exercise.(Lower panel) Visualization of the image data used for segmentation. The participant-specific anatomy of the aorta was segmented from 3D SSFP (steady-state free precession) images (A,C). If the respective participant was treated using a stent, additional image information from black blood MR sequences (D) was used to improve the segmentation of the stented region of the aorta. An example from only 3D SSFP images is shown in panel (B), whereas a combined segmentation of a previously stented patient is shown in panel (E). Computational fluid dynamics (CFD) simulation: Numerical simulations for calculation of patient specific hemodynamics at rest and during exercise were performed using an approach that was previously validated against in-vivo catheter-based measurements as well as 4D-flow-MRI measurements. At the descending aorta, the maximal volume flow rate was measured using the 4D QF sequence during rest and exercise was applied as an outlet boundary condition. At the ascending aorta, the patient-specific peak systolic velocity vector profiles, which were measured using planar 4D VEC MRI at rest and during exercise, were applied. End Points The primary outcome measure was the pressure gradient across the stenosis at rest and during exercise. Secondary outcomes were wall shear stress (WSS), secondary flow degree (SFD), normalized flow displacement (NFD), cardiac index, stroke volume index and heart rate, at rest and during exercise. Results The analysis was carried out in 20 patients. The baseline characteristics of the included patients are shown in Table 1. Of the 20 patients (13 men, 7 women) included, 3 patients were untreated, 5 had undergone surgical repair by end-to-end-anastomosis, 11 were treated by stent-implantation and one stented patient was also treated surgically. The mean age of included patients was 21.5 ± 13.7 years. No symptoms occurred during exercise. The average workload present during exercise was 83.5 ± 37.8 W. On average, 85.79 ± 10.28% of the calculated target heart rate was reached during exercise. Patients’ systolic blood pressure, measured using cuff-measurements at the arm, significantly increased from rest to exercise (128.45 ± 21.45 to 158.65 ± 33.97 mmHg, p = 0.002). The relative static pressure distributions at rest and during exercise that were calculated using CFD are shown in Fig. 3. The mean trans-stenotic pressure gradient was 17.99 ± 16.61 mmHg at rest and 28.45 ± 22.56 mmHg during stress (Fig. 4). Those patients had lower resting heart rates than the patients who featured a stroke volume increase during exercise (61.2 vs. 89.9 bpm, p < 0.001). Also, with exception of one patient, they all were in the lower part of the cardiac index distribution (3.2 vs. 4.0, p < 0.05 at rest and 4.3 vs. 5.6, p < 0.05 during exercise). No relevant difference in the increase of the trans-stenotic pressure gradient was observed between those two groups (8.9 vs 11.1 mmHg, p = 0.55). The measured maximum volume flow rate in the ascending (rest 407.0 ± 87.3, stress 494.4 ± 225.5 ml/min, p < 0.001) and descending (rest 225.5 ± 76.7, stress 274.8 ± 83.8 ml/min, p = 0.002) aorta significantly increased during exercise. However, the ratio of the peak-systolic volume flow rate measured in the ascending and descending aorta did not change significantly (p = 0.287). An overview of changes in hemodynamic parameters is provided in Table 2. Conclusion In this feasibility study, MRI-ergometry and image-based computational fluid dynamics were combined. This approach allows assessing the individual hemodynamic response to exercise under nearly physiological conditions. As pressure gradients at rest and during physical exercise can be determined noninvasively, it has the potential to serve as an alternative to pharmacological stress testing during cardiac catheterization. While the numerical method used has been validated previously, a thorough validation of the translation towards assessment of pressure gradients during dynamic exercise is required before clinical application. However, as currently no clinical standard for measurement of the trans-stenotic pressure gradient during dynamic exercise exists, this combined approach seems promising. In general, the method has the potential for measuring individual changes in trans-stenotic pressure gradients, aortic flow patterns, the left ventricular response to dynamic exercise, providing valuable information for studying the pathophysiology of aortic coarctation. Currently, those parameters can only be assessed in a very limited matter or cannot be assessed at all during dynamic exercise.
Peripheral venous pressure accurately predicts central venous pressure in the adult Fontan circulation
Peripheral venous pressure accurately predicts central venous pressure in the adult Fontan circulation. Tan W, Small A, Gallotti R, Moore J, Aboulhosn J.Int J Cardiol. 2020 Nov 13:S0167-5273(20)34081-X. doi: 10.1016/j.ijcard.2020.11.007. Online ahead of print.PMID: 33189798 Take Home Points: A higher central venous pressure (CVP) is required to drive pulmonary blood flow in the Fontan circulation, although chronically elevated CVP is associated with long-term Fontan complications. Peripheral venous pressure (PVP) has previously been shown to be a relatively robust non-invasive surrogate for CVP in pediatric Fontan patients. This study of adult Fontan patients showed a PVP measurement cutoff 14 mmHg was associated with 100 % sensitivity and 55 % specificity for detecting elevated Fontan pressure. PVP measurement may be a useful screening tool to identify high-risk Fontan patients with elevated CVP, with reassurance for those with a PVP less than 14 mmHg, and consideration of further evaluation indicated for those with elevated PVP. Commentary from Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch: Patients with a Fontan circulation lack a subpulmonary ventricle and require a higher central venous pressure (CVP) to drive pulmonary blood flow. The long-term consequences of higher CVP can include liver cirrhosis and protein losing enteropathy, and mortality has been reported to be higher amongst those with a high CVP compared to those with lower CVP. Pulmonary artery pressure cannot be estimated non-invasively by traditional means in the Fontan circulation. Peripheral venous pressure (PVP) has been demonstrated to be a good surrogate for CVP in patients with acquired heart disease, while studies in pediatric Fontan patients have reported correlation between PVP and CVP. The current study aimed to compare PVP and CVP in adult Fontan patients undergoing cardiac catheterization, with the hypothesis that correlation between these measurements would be reproducible and robust, providing a non-invasive technique to estimate CVP in the outpatient setting. This was a single-centre, prospective, cross-sectional study of adult Fontan patients undergoing clinically indicated cardiac catheterization. All adult patients (age 18 years) were included, and those with a known stenosis or obstruction of either the Fontan pathway or an upper extremity vein were excluded. A total of 43 cases were included. Catheterisation was performed under general anaesthetic. A peripheral intravenous line was placed in an upper extremity vein. Central venous pressure was measured at the superior vena cava level using a 5F – 7F wedge pressure catheter. Equipment was meticulously zeroed prior to measurements, and catheter location confirmed with fluoroscopy. Peripheral venous pressure was measured immediately after CVP measurement by transferring the same pressure transducer, or by using pressure tubing attached to a 3-way stopcock that was attached to the pressure transducer. The peripheral IV catheter was positioned at the level of the mid-axillary line. Both CVP and PVP measurements were recorded with an Edwards TruWave pressure transducer. Linear regression and a Bland-Altman plot analysis for differences were performed. Receiver operator characteristic (ROC) curve for PVP was created, using CVP of 14 mmHg or higher as a cutoff. Table 1 demonstrates baseline demographics and patient characteristics in those undergoing cardiac catheterization. Mean age was 30.7 years, and 24 years post original Fontan surgery. Mean CVP was 17.3 mmHg (SD 4.7 mmHg, range 9 – 30 mmHg), and mean PVP was 18.4 mmHg (SD 5 mmHg, range 9 – 35 mmHg). PVP was strongly correlated to CVP (figure 1): Bland-Altman plot of PVP and CVP showed that PVP overestimated CVP by a mean of 1.2 mmHg (95% CI 0.47 – 1.9 mmHg) with limits of agreement between CVP and PVR from -5.2 to +2.8 mmHg: PVP measurement cutoff 14 mmHg was associated with 100 % sensitivity and 55 % specificity for detecting elevated Fontan pressures. This corresponded to a 100 % negative predictive value and 84 % positive predictive value for the identification of elevated invasive Fontan pressures. This study has found a very strong correlation between PVP and CVP in an older cohort of Fontan patients with more comorbidities and higher Fontan pressures than several other previous studies. PVP measurement may be a useful screening tool to identify high-risk Fontan patients with elevated CVP, with reassurance for those with a PVP less than 14 mmHg, and consideration of further evaluation suggested for those with elevated PVP. An important caveat to the extrapolation of these findings to the outpatient setting is the data arising from intubated and sedated patients; study in awake patients is clearly required before PVP measurement can be routinely recommended in Fontan patients.
Time Course of Ventricular Remodeling after Atrial Septal Defect Closure in Adult Patients. Bae YH, Jang WS, Kim JY, Kim YS.Korean J Thorac Cardiovasc Surg. 2020 Nov 18. doi: 10.5090/kjtcs.20.098. Online ahead of print.PMID: 33203805 Take Home Points: In patients post-surgical ASD repair, the RV volumes were markedly decreased by one month post-op, and continued to decrease (though at a slower rate) by one year. The RV remodeling however did not result in complete normalization by one year. The Late Gadolinium Enhancement (LGE) on CMR in most patients did not improve / resolve at one year post-op. Commentary from Dr. Blanche Cupido (Cape Town, South Africa), section editor of ACHD Journal Watch: Atrial septal defects represent the most common form of congenital heart disease (10-15%). A Qp:Qs ratio of over 1.5 is an indication for percutaneous or surgical closure. Even post closure, there remains an increased risk of arrythmias with potential neurological complications. In light of this, cardiac chamber remodeling may be an important determinant of long-term outcomes. This is a single center study conducted at a tertiary cardiology unit in Korea aimed at assessing ventricular remodeling post-ASD repair by utilizing cardiac magnetic resonance imaging (CMR). Patients who underwent surgical ASD closure between November 2017 and January 2019 and had consented for CMR were included – a total of 13 patients. Clinical, demographic and echocardiography data was obtained from folder review. All patients had CMR imaging pre-operatively, at one month post-op and at 1 year post op. The median age at the time of surgery was 51.4 years. Pre-operative symptoms included chest pain (38.5%, n=5), dyspnoea (30.8%, n=4) and palpitations (15.4%, n=2). None of the patients had atrial fibrillation documented prior to surgery. Of the 13 patients, 12 had an ASD patch closure and one a primary closure. No early or late surgical mortality nor any surgery-related morbidity was noted. At one year follow-up, all but one patient showed resolution of symptoms. The pre-operative NT proBNP showed a trend (non-significant) to increase at one month post-op (83pg/ml to 167pg/ml, p=0.059) and then a reduction by one year post-op to 105.5pg/ml (p=0.118). The median pre-operative Qp:Qs ratio was 2.3 and this correlated positively with RV size parameters (RVEDVi: r=0.862, p=0.001; RVESVi: r=0.784, p=0.004), but did not correlate with LV size parameters. RVEF and LVEF negatively correlated with RVESVi (r=-0.626, p=0.022) and LVESVi (r=-0.743, p=0.004) respectively. RVEF and RVEDVi did not show a meaningful correlation (r=-0.328l p=0.274). No significant differences were seen between NT-pro-BNP levels and any of the CMR parameters (p >0.05 for all). The pre-operative mean RVEDVi and RVESVi showed a significant reduction at 1 month. The RVEDVi and RVESVi further decreased by 1 year, but the rate of decrease was slower (table 2 below). Tricuspid valve regurgitation (TVR) also showed a decrease over time. The pre-operative LVEDVi and LVESVi increased at one month and then remained unchanged at one year. There was no significant change in LVEF at one month or one year follow-up. Late gadolinium enhancement was detected in 12 out of the 13 patients on the pre-operative CMR. At the RV basal septum insertion point. In 7 patients (53.8%) this was still present at the same intensity at one year follow-up.
Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients
Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients. Freisinger E, Gerß J, Makowski L, Marschall U, Reinecke H, Baumgartner H, Koeppe J, Diller GP.Eur Heart...
Assessment of hemodynamic responses to exercise in aortic coarctation using MRI-ergometry in combination with computational fluid dynamics
Assessment of hemodynamic responses to exercise in aortic coarctation using MRI-ergometry in combination with computational fluid dynamics. Schubert C, Brüning J, Goubergrits L, Hennemuth A, Berger F, Kühne T, Kelm M.Sci Rep. 2020 Nov 3;10(1):18894. doi:...
Peripheral venous pressure accurately predicts central venous pressure in the adult Fontan circulation
Peripheral venous pressure accurately predicts central venous pressure in the adult Fontan circulation. Tan W, Small A, Gallotti R, Moore J, Aboulhosn J.Int J Cardiol. 2020 Nov 13:S0167-5273(20)34081-X. doi: 10.1016/j.ijcard.2020.11.007. Online ahead of...
Time Course of Ventricular Remodeling after Atrial Septal Defect Closure in Adult Patients. Bae YH, Jang WS, Kim JY, Kim YS.Korean J Thorac Cardiovasc Surg. 2020 Nov 18. doi: 10.5090/kjtcs.20.098. Online ahead of print.PMID: 33203805 Take Home Points: In...