State-of-the-Art Lecture on Diastolic Blood Pressure: Should We Care?

Messerli F, from the Swiss Cardiovascular Center, University of Bern, Switzerland presented one of the most informational and illuminating talks of the day on the topic, “Diastolic blood pressure (DBP) – should we care?” at the European Society of Cardiology 2021 Congress. 

R.D. Kennedy in Modern Geriatrics in 1974 stated that DBP of up to 120 mmHg in symptomless elderly hypertensive is not an indication for therapy. The first principle of the therapy of hypertension is the knowledge of when to treat and when not to treat. For instance, a woman who has tolerated her DBP of 120 for ten years without symptoms or deterioration does not need immediate treatment for hypertension. DBP has been abandoned for ages and, systolic blood pressure (SBP) is all that matters. Usual BP is strongly and directly related to vascular and overall mortality without any evidence of a threshold down to at least 115/75 mmHg. The mortality of coronary artery disease (CAD) was found to be highest when SBP was highest and DBP was lowest. The odds of a cardiovascular (CV) event were highest with combined high SBP and low DBP. The preponderance of myocardial infractions (MI) over strokes at low DBP suggests that excessive diastolic hypotension associated with antihypertensive therapy increased CAD risk. The risk of DBP was found to be higher in patients without revascularization than patients with revascularization. The results from the EPHESUS trial indicated that myocardial reperfusion reverses the J-curve association of CV risk and DBP in patients with left ventricular dysfunction and heart failure after MI. Reperfusion eliminates risk at low DBP by maintaining perfusion pressure. For any given DBP, there is an upward shift with CAD obstruction and a downward shift with revascularization. DBP increase is a risk factor for both type 1 and type 2 MI.

Thirty years ago, in severe middle-aged hypertensives, attempts at normalisation of high BP may precipitate as many infarctions as it prevents. The BP in such patients should seldom be reduced to diastolic levels <104-110 mmHg. In today’s scenario, evidence from the ISCHEMIA trial suggests that revascularising asymptomatic patients with stable CAD confer little benefits. The question needs to be answered is when there is an urgent need for low BP in patients with stable CAD, should coronaries be not revascularised ‘prophylactically’ even when CAD has remained asymptomatic?

 

Individualizing the Target Diastolic Blood Pressure in Patients Being Treated for Hypertension and Diabetes

Sobieraj P, from presented a session on  “Individualizing the Target Diastolic Blood Pressure in Patients Being Treated for Hypertension and Diabetes” at the ESC Congress 2021.  

As pertthe European Society of cardiology 2018 guidelines, treatment targets in hypertension and diabetes differs for systolic blood pressure (SBP) as per the age group. For patients aged 18-65 years the SBP target is 120-130 mmHg; for patients aged 65-79 years the SBP target is 130-139 mmHg; and for patients aged > 80 years the SBP target is 130-139 mmHg. Whereas the target for diastolic blood pressure (DBP) remains 70-79 mmHg suggesting lower the better. Diabetes and hypertension together are responsible for greater cardivascular risk, increased arterial stiffening, increased pulse pressure and lower DBP <70 mmHg during treatment. A post-hoc analysis of Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD-BP) was conducted where the intensive SBP lowering (<120 mmHg) when compared to standard BP reduction (<140 mmHg) was not associated with reduced risk for primary clinical endpoint (nonfatal myoacrdial infarction, nonfatal stroke, or cardiovascular death [Hazard ratio: 0.88]). The event rate for patients < 65 years without cardiovascular disease has remained low at all levels of DBP, whereas for patients with cardiovascular disease has been the lowest between 70-80 mmHg. The event rate for patients > 65 years without cardiovascular disease has remained steady at all levels of DBP, whereas for patients with cardiovascular disease has decreased as the targets approched closer to 80 mmHg.

Optimal DBP treatment target in subjects with cardiovascular disease and diabetes is slightly lower than currently recommended range of 70-80 mmHg. Diastolic blood pressure values in the range of 70-80 mmHg should not be recommended as the treatment target for subjects with diabetes and no history of CVD.

 

Optimal Control of Symptoms: Crucial Questions on Timing and Patients’ Profiles

Leng DK, presented his insights on the topic, “Optimal Control of Symptoms: Crucial Questions on Timing and Patients’ Profiles” at the European Society of Cardiology conference 2021.  From 2103 there has been a change in the nomenclature of the ESC guidelines from stable coronary artery disease to chronic coronary syndromes (CCS). CCS are now recognised as having a wider clinical spectrum of presentations such as chronic long-term subclinical disease with interjections of major adverse CV events; different trajectories depending on patients differing risk profile and ranging from silent ischaemia to chest pain syndromes of non-obstructive ischaemia to significant coronary flow-impaired atherosclerotic cardiovascular disease (ASCVD). The goals of management of CCS includes preventing myocardial infarction or death and relieving anginal symptoms with a reduction in ischaemia. The ACC/AHA/ACP-ASIM and the ESC guidelines recognise optimal medical therapy (OMT) for patients with CCS. OMT is use of drugs and therapies adapted to each patient’s characteristics and preferences. Other than the traditional 1st line anti-anginal drugs with haemodynamic actions, used in stepwise fashion, there should be a greater role for non-haemodynamic agents with metabolic actions that can improve the myocardial energy utilisation or decrease cardiomyocyte metabolic dysfunction, thus achieving more complete alleviation of myocardial ischaemia and angina, now increasingly recognised with different causes of CCS. Second line add-on anti-ischaemic drugs (long acting nitrates, trimetazidine, and to a lesser extent ivabradine) may prove beneficial in combination with a beta-blocker or a CCB as first line therapy. A diamond approach to personalised treatment of angina can be adopted. Metabolic agents can be added on early and/or to complement other hemodynamic drugs to achieve better angina control in many of the ischaemic symptoms like coronary artery spasm and microvascular angina etc.

Personalise and individualise most appropriate OMT for each patient based on comorbities/patient features. Use early add-on combination anti-anginals (trimetazidine or ranolazine) that are proven to reduce the angina frequency and the decrease the use of nitrates and improve the quality of life.

 

CCS Therapies are Long-Term Treatments: Can we Improve the Effectiveness of Therapies for Ischemic Heart Diseases?

Nedoshivin A, from St. Petersburg, Russian Federation presented his take on the topic, CCS Therapies are Long-Term Treatments: Can we Improve The Effectiveness of Therapies For Ischemic Heart Diseases” at the European Society of Cardiology conference 2021.  

Patients with angina commonly present with comorbidities. Peripheral artery disease, asthma, low heart rate (HR) and low blood pressure (BP) limit the use of beta-blocker and calcium channel blocker is not indicated in heart failure. The treatment outcomes vary from physicians to patients. Patient factors to be considered as parameter for effectiveness of therapies include subjective goals, quality of life, and treatment satisfaction. Optimal treatment can be defined as the treatment that satisfactorily controls symptoms and prevents cardiac events associated with CCS with maximal patient adherence and minimal adverse events. In patients with angina and/or dyspnea and coronary artery disease, use of nicorandil, ranolazine, ivabradine, or trimetazidine should be considered as a second-line treatment to reduce angina frequency and improve exercise tolerance in subjects who cannot tolerate, have contraindications to, or whose symptoms are not adequately controlled by beta-blockers, CCBs and long-acting nitrates. In patients with baseline low heart rate and low BP, ranolazine or trimetazidine may be considered as a first-line drug to reduce angina frequency and improve exercise tolerance. In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, trimetazidine, nicorandil, ivabradine, and trimetazidine) may be considered for first-line treatment according to heart rate, BP, and tolerance. The ischemic cardiac cell is a smart therapeutic target in patients with angina. Trimetazidine bypasses the potential mechanisms causing ischaemia. Trimetazidine provides angina alleviation as soon as within 2 weeks whatever the haemodynamic background anti-angina therapy. 50% of the angina patients have HR ≥ 70 beats/minute in spite of beta-blockers therapy. Ivabradine provides specific heart rate reduction while preserving global cardiac function without coronary vasoconstriction. 

To improve the effectiveness of therapies for ischaemic heart diseases, it is important to consider: multiple origin of the disease; patient profile and comorbidities; treatment adherence should be considered and adaptation of the guidelines to each patient profiles.

 

MASTER DAPT: Dual Antiplatelet Therapy After Coronary Stenting in High Bleeding Risk Patients

Valgimigli M, presented results from the investigator-initiated, open-label MASTER DAPT trial at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 which compared an abbreviated vs. a standard duration of antiplatelet therapy following bioresorbable polymer-coated sirolimus-eluting stent implantation in patients with acute or chronic coronary syndrome who fulfilled one or more high bleeding-risk criteria.

Eligible patients who were free from ischaemic and bleeding events were randomised 1:1 to receive abbreviated or standard DAPT after a mandatory 30-day DAPT run-in phase following percutaneous coronary intervention (PCI). Abbreviated treatment comprised single antiplatelet therapy until study completion, except for patients receiving clinically indicated oral anticoagulation, who continued single antiplatelet therapy up to 6 months after PCI. Standard treatment comprised DAPT continuation for at least 5 additional months (6 months after PCI) or, for those receiving clinically indicated oral anticoagulation, for at least 2 additional months (3 months after PCI) and with continuation thereafter of single antiplatelet therapy. This was a noninferiority study with consequent superiority analysis. The three ranked coprimary outcomes were: 1) net adverse clinical events (the composite of all-cause death, myocardial infarction [MI], stroke, and major or clinically relevant non-major bleeding); 2) major adverse cardiac and cerebrovascular events (MACCE, the composite of all-cause death, MI and stroke); and 3) major or clinically relevant non-major bleeding happening among randomisation and 335 days, described as Bleeding Academic Research Consortium type 2, 3 or 5 bleeding.

A total of 4,579 patients from 30 countries were randomised at a median of 34 days following PCI. The mean age was 76 years, 69.3% were men, 36.2% were acquiring concomitant oral anticoagulation, and 48.3% underwent PCI for acute coronary syndrome (ACS). There was a mean of 2.1 high bleeding-risk criteria per patient. Abbreviated DAPT was noninferior to standard DAPT regarding net adverse clinical events and MACCE. Net adverse clinical events happened in 7.5% of patients in the abbreviated DAPT group and 7.7% of patients in the standard DAPT group (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.78 to 1.20), for a risk difference of −0.23% (95% CI −1.80 to 1.33; p<0.001 for noninferiority). MACCE occurred in 6.1% of patients of abbreviated DAPT group and 5.9% of patients of standard DAPT group (HR 1.02; 95% CI 0.80 to 1.30), for a risk difference of 0.11% (95% CI −1.29 to 1.51; p=0.0014 for noninferiority). Abbreviated DAPT was better to standard DAPT in terms of major or clinically relevant non-major bleeding events (6.5% vs. 9.4%, respectively; HR 0.68; 95% CI 0.55 to 0.84; p<0.001 for superiority), with a risk difference of −2.82% (95% CI −4.40 to –1.24).

1 month of DAPT following PCI continued the ischaemic advantages of treatment although decreasing the risk of bleeding is remarkable. The findings can notify therapy decisions on DAPT at 1 month after PCI in patients at high risk for bleeding without post-procedural ischaemic events, including those with clinical or angiographic high ischaemic risk features.

ENVISAGE-TAVI AF: Edoxaban vs. Vitamin K Antagonists After TAVI in Patients with Atrial Fibrillation

The data on the safety of direct-acting oral anticoagulants compared with vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) after successful transcatheter aortic valve implantation (TAVI) is limited. Dangas G, presented results from the multicentre, open-label ENVISAGE-TAVI AF study at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 in which patients with AF and an anticoagulation indication were randomised to obtain edoxaban or the locally available VKA (warfarin or its analogues), each administered among 12 hours and 5 days after TAVI.

The primary efficacy endpoint was the occurrence of net adverse clinical events (NACE), a composite of all-cause death, myocardial infarction, ischaemic stroke, systemic thromboembolism, valve thrombosis and major bleeding (as defined by the International Society on Thrombosis and Haemostasis [ISTH]). The primary safety endpoint was the occurrence of ISTH-defined major bleeding. The average age of the 1,426 participants was 82 years and 47.5% were women. Comorbidities were common: 83–87% patients showed congestive heart failure, 39–42% showed coronary artery disease, and approximately 17% showed a previous stroke or transient ischaemic event. After average follow-up of 18 months, edoxaban exhibited noninferiority to VKAs for the primary efficacy endpoint. NACE rates were 17.5% per year in the edoxaban group and 16.5% per year in the VKA group (hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.85 to 1.31; p=0.01 for noninferiority). But, edoxaban group showed higher risk of major bleeding than VKA group (HR 1.40; 95% CI 1.03 to 1.91), with rates of 9.7% per year and 7.0% per year, respectively. The higher risk was chiefly because of gastrointestinal bleeding. In secondary analyses, patients in the edoxaban group who needed a downward dose adjustment and those not prescribed oral antiplatelet therapy showed a similar rate of major bleeding as the VKA group.

ENVISAGE-TAVI AF recommends that therapy with edoxaban can be beneficial in the treatment of this high-risk population of patients with AF following TAVI. It seems that lowering the edoxaban dosage when signified and avoiding patients on mandatory antiplatelet treatment is valid safety advice from a clinical point of view.

 

A Randomised Control Trial of TeleClinical Care – A Smartphone-app Based Model of Care for Heart Failure and Acute Coronary Syndromes

Acute coronary syndrome (ACS) and heart failure (HF) often lead to hospitalisation and readmissions. A novel smartphone app-based model of care (TeleClinical Care – TCC), developed to support patients after ACS or HF admission, was evaluated in this randomised control trial. Indraratna P, presented a session at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 which assessed the intervention, clinical outcomes, cost-effectiveness and user satisfaction. The primary endpoint was the incidence of 30-day readmissions. In contrast, secondary endpoints were six-month cardiac and all-cause readmissions, mortality, major adverse cardiovascular events (MACE), cardiac rehabilitation (CR) completion, medication adherence, serum low-density lipoprotein (LDL-C), quality of life, blood pressure, body mass index, waist circumference and six-minute walk distance.

164 people (mean age 61.5; 79% male) were randomly assigned to TCC plus normal treatment (n=81) or standard care alone (n=83) and followed up for six months. A Bluetooth-enabled device was used daily to measure weight, heart rate, blood pressure, and physical activity in the intervention arm. The patient’s smartphone and a secure web-server received the readings (KIOLA). At discharge, each parameter had custom thresholds. The programme sent informative push messages and sent abnormal values to a monitoring team for care adjustments.

Average data transmission days per patient were 64.2 27.5 percent. A total of 565 notifications were received, with 16% leading to further inquiry, consultation, or a change in care. It was the same in both groups (11 readmissions each). However, the intervention arm had fewer six-month readmissions (21 vs. 41, HR = 0.40, 95 percent CI 0.16-0.95, P = 0.03). TTC enhanced CR completion (39 percent vs. 18 percent, P = 0.025) and drug adherence (75 percent vs. 50 percent, P = 0.002). Mortality, MACE, LDL-C, quality of life, and other physical characteristics were not different. Each prevented readmission cost EUR 4015. Users gave it 4.56/5. Modeling showed that a larger patient population would result in lower total expense..

Use of TeleClinical Care improved patient care, reduced readmissions, improved patient adherence and was predicted to be cost-effective.

 

Age- and Sex-Specific Rates of Heart Failure and other Adverse Cardiovascular Outcomes in Systemic Sclerosis

In patients with systemic sclerosis (SSc), age at disease onset and sex alter the disease course. Sun GL, presented a session at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 which investigated the long-term rates of HF and other adverse cardiovascular outcomes in a nationwide cohort of patients with SSc compared with the background population without SSc according to Age and sex, separately.

Using Danish nationwide registries, all patients aged >18 years with newly diagnosed SSc (1996-2018) were identified. SSc patients were matched at a 1:4 ratio by Age, sex, and comorbidities with controls from the background population. Rates of outcomes including arrhythmias, myocardial infarction, ischemic stroke, venous thromboembolism and pulmonary hypertension, according to Age and sex, were compared.

1,569 patients were matched with 6,276 controls from the background population (median age 55 years, 80.4% women). A higher rate of HF in both women (HR 2.99 [95% CI, 2.18-4.09]) and men (HR 3.01 [1.83-4.95]) (Pfor interaction=0.88) with similar findings for other cardiovascular outcomes was observed in SSc patients. SSc was associated with an increased rate of HF in patients younger than 55 years (HR 4.14 [2.54-6.74]) and ≥55 years (HR 2.74 [1.98-3.78]) and other cardiovascular outcomes.

 An increased long-term rate of cardiovascular outcomes was observed with systemic sclerosis than a matched background population, irrespective of age and gender.

 

An in-vitro Model of Stiffened Aortic Valves to Develop an Iso-stiffness-lines Graph for Severity Evaluation Aortic Stenosis

Aortic stenosis (AS) is diagnosed by assessing its maximal opening area (OA), the behavior of which is depends on transvalvular flow. This transvalvular flow could be low in case of low-flow, low-gradient AS. As per the current guidelines, for the assessment of AS instead of flow a stroke volume must be considered. Buffle E, presented a session at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 which aimed to create a graphical representation of the OA versus flow for various valve stiffness values to eventually build a model with iso-stiffness lines.

A high speed camera was used to film the ejection of a harvested swine aortic valve (2000Hz). Measurement of the instantaneous flow via the aortic valve at ten different mean flow rates (from 0.5 to 5.0 liters/min). OA and flow were split by the area of the left ventricular outflow tract to accommodate for valve sizes (LVOT). For each OA, the flow was depicted after intersignal delay correction. In order to account for the time lag between flow initiation and valve opening caused by valve ballooning, only the 5 percent highest instantaneous flow rates (for each of the 10 mean flow rates) were included. For each of the three stiffness categories (a, b, c), the valve was treated with a protein cross-linking agent (formaldehyde).

An asymptotic appearance of the flow-OA relationship was observed. Flattening of this relationship with increasing valve stiffening was demonstrated which visually matched well simulated data generated with a sigmoid model. All flow/OA pairs at different stiffness grades were successfully obtained. This allows to fit a sigmoid function capturing the flow-OA relationship for each stiffness grade. The resulting iso-stiffness line for classifying valve stenosis grade can be drawn in one single graph.

For patient with low-flow and low-gradient AS, simplified grading system of aortic stenosis, irrespective of the flow and the size of the valve can be achieved.

  

Arrhythmia Patterns in Patients with COVID-19 Infection During and Post Hospitalization Detected via a Patch-based Mobile Cardiac Telemetry System

Coronavirus infection (COVID-19) is the origin of the current world-wide pandemic. Cardiovascular complications happen in 20-30% of patients with COVID-19 infection incorporating myocardial injury and arrhythmias. There is limited information regarding recent understanding of specific arrhythmia type and frequency. A patch-based cardiac monitoring system acquired emergency Food and Drug Administration (FDA) approval for inpatient monitoring in response to COVID-19 pandemic and overwhelmed hospital critical care and telemetry recourses. A patch-based cardiac telemetry system has been shown to be beneficial for patient treatment in the COVID-19 pandemic and yields detailed examination of cardiac rhythms. Reynbakh O, presented a session at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 which assessed arrhythmia type and frequency in patients with COVID-19 infection, recognising arrhythmia patterns across time in hospitalization and following discharge.

A prospective group study in the COVID-19 pandemic was executed. Patients hospitalized with COVID-19 infection who had a patch-based mobile telemetry device placed for cardiac monitoring were included. A quantitative evaluation incorporating type, frequency and duration of diagnosed arrhythmias was executed at the end of the monitoring period.

A total of 103 patients hospitalized with COVID-19 diagnosis experienced monitoring. Quantitative reports for 59 patients were available for evaluation, between those 59% were males, median age 65 (IQR 56-76) yrs. Mean wear time was 6.8±5.0 days. Arrhythmias were diagnosed in 72.9% of patients. Majority of arrhythmias were SVT (59.3% of patients) and AF (22.0%). Episodes of AF duration >30 min were diagnosed in 12 patients. New onset AF was noted in 15.0% of patients and was substantially correlated with age (OR 1.4 for 5 yrs difference; 95% CI 1.01-2.05). 18.7% of patients showed brady arrhythmias (2nd degree, 3rd degree AV bock, pause≥3 seconds). Arrhythmias were constantly diagnosed throughout the monitoring period in 52.9%-89.5% of patients daily (Figure). 3 patients (33.3%) from 9 patients who were discharged with continued patch monitoring, showed arrhythmic events in their outpatient monitoring period.

A majority of patients hospitalized with COVID-19 infection showed arrhythmias diagnosed with patch cardiac monitor. Arrhythmias were noticed via hospitalization with a compatible daily frequency. Patients continued to show cardiac arrhythmias following hospital discharge of a type like that seen in hospitalization. New onset AF often happened and was correlated with older age. Inpatient application of a patch cardiac telemetry with continued monitoring as outpatient is attainable and efficacious in diagnosing occult arrhythmias in patients with COVID-19 infection.

   

Validation of a Pandemic-proof, Decentralized Cardiovascular Trial: Scalable Design Produces Rapid Recruitment, High Engagement and Protocol Adherence in DeTAP (Decentralized Trial in Afib Patients

The COVID-19 pandemic has reduced clinical trial activity substantially. Decentralized clinical trial (DCT) designs may decrease cost, expand trial access, and decrease exposure risk for patients and staff. However, it is still not known that whether such designs can be used for large, pivotal drug trials. Dash R, presented a session at the European Society of Cardiology (ESC) Congress 2021: The Digital Experience on 28th August 2021 which informed whether a large phase 3 Cardiovascular DCT can accomplish high quality trial results and also withstand health crises such as the COVID-19 pandemic. The DeTAP (Decentralized Trial in Afib Patients) was a single-arm, observational study that combined a suite of digital health technologies, incorporating paired home sensor devices, into a 100% virtual trial experience for atrial fibrillation (AF) patients on anticoagulation.

100 AF patients across age 55 on oral anticoagulation (OAC) were recruited via traditional procedures or by social media ads placed California-wide. Patients completed an online pre-screening, uploaded their active OAC prescription, and completed an e-consent through SMS message link. Participants downloaded a customized study app to combine surveys and data from study-supplied wireless blood pressure (BP) and 6 lead EKG sensors (Figure 1A). Participants completed pre- and post-study engagement surveys, weekly OAC adherence surveys, 4 study televisits, 4 ECG/BP readings, and 4 post-study surveys across a 6 month period. The primary endpoints were protocol engagement-based assessments that analysed percent completion of: 1) televisits 2) surveys, 3) ECG/BP readings needs. Secondary endpoints were the % changes in: 1) OAC adherence (OACA), 2) nuisance bleeding (NB), 3) individual patient engagement surveys.

100 participants were enrolled in 26 days (traditional: 6 in 2 weeks; social media: 94 in 12 days) with a dramatic surge in enlistment operated using social media ads (Figure 1B, Table). A recruitment overflow hapened with >200 eligible candidates on a waitlist. All key study completion metrics exhibited high compliance: televisit (91%); surveys (85%); ECG/BP completion (90%). Altogether OACA was unchanged, however for patients who reported low initial OACA, there was substantial enhancement at 6 months (85±16% to 98±6%; p=0.002). 47 participants (57%) reported NB, which did not associate with OACA. Participant engagement measure scores (PAM-13) moved higher (baseline, 70%; 6 months, 74%, p=0.32). Finally, study participants showed active interest in participating in a larger experimental drug DCT study (90%) in the future.

The DeTAP study showed that a decentralized CV medical intervention trial is advantageous and can accomplish rapid recruitment, high study retention, physiologic and adverse event reporting, and high study engagement through the proper combination of digital technologies and a dedicated DCT study coordination exertion. These results could be enlightening for virtualizing large pivotal clinical trials at scale.