Prehospital Period in Patients with COVID-19: Cardiovascular Comorbidity and Pharmacotherapy During the First Epidemic Wave (Hospital Registry Data)

Aim. Based on the data from the register of patients with COVID-19 and community-acquired pneumonia (CAP), analyze the duration of the prehospital period, cardiovascular comorbidity and the quality of prehospital pharmacotherapy of concomitant cardiovascular diseases (CVD).Material and methods. Patients were included to the study which admitted to the FSBI "NMHC named after N.I. Pirogov" of the Ministry of Health of the Russian Federation with a suspected or confirmed diagnosis of COVID-19 and/or CAP. The data for prehospital therapy, information from medical histories and a patients’survey in the hospital or by telephone contact 1-2 weeks after discharge were study. The duration of the prehospital stage was determined from the date of the appearance of clinical symptoms of coronavirus infection to the date of hospitalization.Results. The average age of the patients (n=1130; 579 [51.2%] men and 551 [48.8%] women) was 57.5±12.8 years. The prehospital stage was 7 (5,0; 10,0) days and did not differ significantly in patients with the presence and absence of CVD, but was significantly less in the deceased than in the surviving patients, as well as in those who required artificial lung ventilation (ALV). 583 (51.6%) patients had at least one CVD. Cardiovascular comorbidity was registered in 222 (42.7%) patients with hypertension, 210 (95.5%) patients with coronary heart disease (CHD), 104 (91.2%) patients with atrial fibrillation (AF). The inclusion of non-cardiac chronic diseases in the analysis led to an increase in the total proportion of patients with concomitant diseases to 65.8%. Approximately a quarter of hypertensive patients did not receive antihypertensive therapy, a low proportion of patients receiving antiplatelet agents and statins for CHD was revealed – 53% and 31.8%, respectively, anticoagulants for AF – 50.9%.Conclusion. The period from the onset of symptoms to hospitalization was significantly shorter in the deceased than in the surviving patients, as well as in those who required ALV. The proportion of people with a history of at least one CVD was about half of the entire cohort of patients. In patients with CVD before COVID-19 disease, a low frequencies of prescribing antihypertensive drugs, statins, antiplatelet agents and anticoagulants (in patients with AF) were recorded at the prehospital stage.

Effects of Antihypertensive Drugs Use on Risk and Prognosis of Colorectal Cancer: A Meta-Analysis of 37 Observational Studies

Background: Antihypertensive drugs might play a key role in the risk and poor prognosis of colorectal cancer. However, current epidemiologic evidence remains inconsistent. The aim of this study is to quantify the association between antihypertensive drugs and colorectal cancer.Methods: To identify available studies, we systematically searched electronic databases: PubMed, Web of Science, Embase, Cochrane Library. The risk estimates and their corresponding 95% confidence intervals (CIs) were collected and analyzed by using random-effects models. Heterogeneity test and sensitivity analysis were also performed.Results: Overall, 37 observational studies were included in this analysis (26 studies with cohort design, three studies with nested case-control design, and 8 studies with case-control design). Antihypertensive drugs did not present a significant effect on the risk or overall survival of patients with colorectal cancer [Risk ratio (RR) = 1.00, 95% CI: 0.95–1.04; Hazard ratio (HR) = 0.93, 95% CI: 0.84–1.02]. In the subgroup analysis, diuretics use was significantly associated with a worse overall survival of patients with colorectal cancer (HR = 1.27; 95% CI: 1.14–1.40). However, use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was associated with improved progression-free survival of patients who suffered from colorectal cancer (HR = 0.83; 95% CI: 0.72–0.95).Conclusion: Antihypertensive drug usage did not influence the risk and overall survival of patients with colorectal cancer in general. Further investigation reminded us that diuretics use might reduce the overall survival time in colorectal cancer patients, whereas those who took Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers had a longer progression-free survival.

Sex Differences in Spironolactone and the Active Metabolite Canrenone Concentrations and Adherence

We aim to investigate sex differences in blood concentrations of spironolactone and the active metabolite canrenone in resistant hypertension patients. Furthermore, sex differences in adherence for spironolactone and other antihypertensive drugs (AHDs) were studied. The patients in this post hoc study had all participated in a single-blind randomized controlled trial called RHYME-RCT (Dutch Trial Register, NL6736). Concentrations in blood of several AHDs were assessed in RHYME-RCT to investigate adherence to treatment. This allowed for a comparison of drug exposure to spironolactone and canrenone between males and females. In linear regression models, no statistically significant sex differences (N = 35) in spironolactone (B =−10.23, SE = 7.92, p = 0.206) or canrenone (B = 1.24, SE = 10.96, p = 0.911) concentrations after adjustment for dose and time between sampling and intake were found. Furthermore, no statistically significant differences in non-adherence to spironolactone were found between sexes (N = 54, male 15% vs. female 38%, p = 0.100), but non-adherence to spironolactone was associated with non-adherence to other AHDs (p ≤ 0.001). Spironolactone and canrenone concentrations were not different between males and females with resistant hypertension. Although not statistically significant, females were twice as likely to be non-adherent to spironolactone compared to males, and thereby also more likely to be non-adherent to other AHDs.

Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial: Rationale, design and progress

Background: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention. Objectives: The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC “Triple Pill,” three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH. Design: An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130–160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A total of 1500 randomized patients provide 90% power to detect a hazard ratio of 0.5, over an average follow-up of 3 years, according to a total primary event rate (any stroke) of 12% in the control arm and other assumptions. Secondary outcomes include recurrent ICH, cardiovascular events, and safety. Results: Recruitment started 28 September 2017. Up to 31 October 2021, 821 patients were randomized at 54 active sites in 10 countries. Triple Pill adherence after 30 months is 86%. The required sample size should be achieved by 2024. Conclusion: Low-dose Triple Pill BP lowering could improve long-term outcome from ICH.

A Non-Invasive Method for Detection of Antihypertensive Drugs in Biological Fluids: The Salivary Therapeutic Drug Monitoring

Objectives: Arterial hypertension is still the most frequent cause of cardiovascular and cerebrovascular morbidity and mortality. Antihypertensive treatment has proved effective in reduction of cardiovascular risk. Nevertheless, lifestyle interventions and pharmacological therapy in some cases are ineffective in reaching blood pressure target values, despite full dose and poly-pharmacological treatment. Poor adherence to medications is an important cause of treatment failure. Different methods to assess therapeutic adherence are currently available: Therapeutic drug monitoring in biological fluids has previously demonstrated its efficacy and reliability. Plasma and urine have been already used for this purpose, but they may be affected by some practical limitations. Saliva may represent a feasible alternative.Methods: Fourteen antihypertensive drugs and two metabolites were simultaneously tested in plasma, urine, and saliva. Tested molecules included: atenolol, nebivolol, clonidine, ramipril, olmesartan, telmisartan, valsartan, amlodipine, nifedipine, doxazosin, chlorthalidone, hydrochlorothiazide, indapamide, sacubitril, ramiprilat, and sacubitrilat. Therapeutic drug monitoring was performed using ultra-high performance liquid chromatography, coupled to tandem mass spectrometry (UHPLC-MS/MS). The method has been preliminarily evaluated in a cohort of hypertensive patients.Results: The method has been validated according to US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The application on a cohort of 32 hypertensive patients has demonstrated sensibility and specificity of 98% and 98.1%, respectively, with a good feasibility in real-life clinical practice.Conclusion: Saliva may represent a feasible biological sample for therapeutic drug monitoring by non-invasive collection, prompt availability, and potential accessibility also in out-of-clinic settings.

Management of renin-angiotensin-aldosterone inhibitors and other antihypertensives and their clinical effects on pre-anesthesia blood pressure

Background: Blood pressure fluctuations appear more significant in patients with poorly controlled hypertension and are known to be associated with adverse perioperative morbidity. In the present study, we aimed to determine the effects of antihypertensive drug treatment strategies on preanesthetic operating room blood pressure measurements.Methods: A total of 717 patients participated in our study; 383 patients who were normotensive based on baseline measurements and not under antihypertensive therapy were excluded from the analysis. The remaining 334 patients were divided into six groups according to the antihypertensive drug treatment. These six groups were examined in terms of preoperative baseline and pre-anesthesia blood pressure measurements. Results: As a result of the study, it was observed that 24% of patients had high blood pressure precluding surgery, and patients using renin-angiotensin-aldosterone system inhibitors (RAASI) had higher pre-anesthesia systolic blood pressure than patients using other antihypertensive drugs. Patients who received beta-blockers were also observed to have the lowest pre-anesthesia systolic blood pressure, diastolic blood pressure, and mean blood pressure, compared to others. Conclusions: Recently, whether RAASI should be continued preoperatively remains controversial. Our study shows that RAASI cannot provide optimal pre-anesthesia blood pressure and lead to an increase in the number of postponed surgeries, probably due to withdrawal of medication before the operation. Therefore, the preoperative discontinuation of RAASI should be reevaluated in future studies.

The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis.

Nanoemulsions for the Delivery of Anti-Hypertensive Drugs

Hypertension refers to an increase in the arterial blood pressure. Most commonly used antihypertensive drugs are available in conventional dosage forms as it offers superior patient compliance. A majority of anti-hypertensive drugs pose bioavailability issues as they belong to BCS class II and BCS class IV categories with poor solubility profile and rate limiting dissolution. Emerging drug delivery technologies like nanoemulsion are found to be promising and safer alternatives for the delivery of anti-hypertensive drugs. Nanoemulsion gained more attention due to favourable properties such as small size, good physical stability, rapid action, drug targeting, prevents photo-degradation, and improved bioavailability. This chapter highlights various aspects of hypertension including its pathophysiology and potential approaches to combat high blood pressure. In addition, the authors thoroughly discussed nanoemulsions and their utility in the oral delivery of anti-hypertensive drugs.