Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S Priming.

BACKGROUND: The Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear. METHODS: In this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting. RESULTS: Homologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration. CONCLUSIONS: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.).

Durability of Immune Responses After Boosting in Ad26.COV2.S-Primed Healthcare Workers.

The emergence of SARS-CoV-2 variants raised questions regarding the durability of immune responses after homologous or heterologous boosters after Ad26.COV2.S-priming. We found that SARS-CoV-2-specific binding antibodies, neutralizing antibodies, and T cells are detectable 5 months after boosting, although waning of antibodies and limited cross-reactivity with Omicron BA.1 was observed.

No association between use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID-19 in the COvid MEdicaTion (COMET) study.

Since the outbreak of SARS-CoV-2, also known as COVID-19, conflicting theories have circulated on the influence of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID-19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID-19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID-19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality.

Evaluation of a group-based online informed consent conversation (eConsent) in participants from a low-risk vaccination clinical trial.

BACKGROUND: Electronic informed consent (eConsent) usage has expanded in recent years in Europe, especially during the pandemic. Slow recruitment rate and limitations in participant outreach are the challenges often faced in clinical research. Given the benefits of eConsent and group counselling reported in the literature, group eConsent was implemented in recruitment for the SWITCH-ON study. We aim to explore the experience of participants who attended group eConsent for the SWITCH-ON study and evaluate its potential for future use. METHODS: SWITCH-ON study aims to analyse the immunogenicity of a healthy population following bivalent COVID-19 booster vaccination. Four hundred thirty-four healthcare workers aged 18-65 were successfully recruited and sent a questionnaire about their experience with group eConsent. Out of 399 completed questionnaires (response rate 92%), 39 participants did not join group eConsent. The remaining 360 responses were included in the final analysis. Quantitative and qualitative data were reported using descriptive statistical analysis and thematic analysis respectively. RESULTS: Participants found that group eConsent was an efficient method that it allowed them to hear each other's questions and concerns and created a sense of togetherness. However, limited privacy, barriers to asking questions in a group, and peer pressure can limit the use of group eConsent. One hundred sixty-five (46%) participants thought that group eConsent was suitable to recruit participants with diseases or conditions, while 87 (24%) reported limitations with this method. The remaining participants suggested that applicability of group eConsent depended on the diseases or conditions of the study population, and one-to-one conversation should always be available. Participants who had experienced both one-to-one and group eConsent shared different preferred consent formats for future studies. CONCLUSION: Group eConsent was positively evaluated by the participants of a low-risk vaccination study. Participants advised using webinars to provide general information about the study, followed by an individual session for each participant, would retain the benefits of group eConsent and minimise the limitations it posed. This proposed setting addresses privacy questions and makes group eConsent easier to implement. TRIAL REGISTRATION: ClinicalTrials.gov NCT05471440 (registered on 22nd of July, 2022).

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters.

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

The combined use of aspirin, a statin, and blood pressure-lowering agents (polypill components) and the risk of vascular morbidity and mortality in patients with coronary artery disease.

BACKGROUND AND AIMS: Patients with established coronary artery disease (CAD) are likely to receive a combination of aspirin, a statin, and blood pressure (BP)-lowering agents. Combining these pharmacologic agents into a cardiovascular combination pill, such as a polypill, could be considered to reduce prescription gaps and nonadherence in high-risk patients. We aimed to evaluate the effect of the concomitant use of aspirin, a statin, and BP-lowering agent(s) in patients with CAD on vascular morbidity and mortality in current clinical practice in an observational study to provide insights in the combination pill concept related to feasibility and applicability. METHODS: In total, 2,706 patients with CAD enrolled in the Second Manifestations of ARTerial disease study were followed for the occurrence of a subsequent vascular event (ie, myocardial infarction, ischemic cerebrovascular accident, vascular death) and all-cause mortality. The relationship between combination therapy and cardiovascular events and all-cause mortality was assessed using Cox proportional hazards regression models to calculate hazards ratios (HRs) with a 95% CI. Both covariate and propensity score adjusting methods were used to reduce confounding by indication. RESULTS: A combination of aspirin, a statin, and ≥1 BP-lowering agent(s) was used by 67% of the patients. During a median of 5.0 years (interquartile range 2.4-10.2 years), 347 vascular events occurred and 162 patients died. Combination therapy with aspirin, statin, and ≥1 BP-lowering agent was associated with a lower risk of myocardial infarction (HR 0.68, 95% CI 0.49-0.96), ischemic cerebrovascular accident (HR 0.37, 95% CI 0.16-0.84), composite vascular end point (HR 0.66, 95% CI 0.49-0.88), vascular mortality (HR 0.53, 95% CI 0.33-0.85), and all-cause mortality (HR 0.69, 95% CI 0.49-0.96) compared with the absence of combination therapy, after adjusting for confounding covariates in a propensity score. The use of 1 or only 2 components of combination therapy was associated with a higher risk for cardiovascular events compared with the combined use of aspirin, a statin, and ≥1 BP-lowering agent(s). CONCLUSION: Two-thirds of the patients with CAD use a combination of aspirin, a statin, and ≥1 BP-lowering agent(s), components of a cardiovascular fixed-dose combination pill. Combination therapy with these agents is associated with a lower risk of vascular events and total mortality. Although treatment effect in observational studies should be interpreted with caution, the results of this study support supposed benefits from combination therapy. However, the effect of fixed-dose combination pill on clinical outcome needs to be demonstrated in randomized clinical trials.

[When will we treat patients with a polypill shortly after myocardial infarction?] / Wanneer gaan we patiënten een 'polypil' geven?

The 'polypill' stands for fixed-dosed combination pills with generic drugs that act on multiple cardiovascular risk factors. Data from randomized controlled trials show consistent beneficial effects of treatment with a polypill on both cardiovascular risk factors and relevant marjor cardiovascular endpoints. However, polypills are not readily available worldwide and only a limited number of polypills is marketed in Europe. Physicians have to embrace polypills in regular care to let the patient benefit from the advantages of the polypill. Licensing more polypills is an essential step to implement these pills in clinical care. Regulatory agencies need to reduce the dossier content requirements for registrations of new fixed-dosed combination pills so generic pharmaceutical companies can expand the number of marketed polypills.

[How to cope with the nocebo effects of statins?] / Nocebo-effecten van statines.

Statins are effective drugs that can reduce the risk of new cardiovascular events. Although in randomized, placebo-controlled trials statins are associated with a low risk of mild muscle complaints such as myalgia, in daily practice up to 30% of patients report complaints attributed to statin use. Two recent studies have shown statin-associated muscle complaints are mainly related to the nocebo effect. The nocebo effect is a decrease in benefit and/or a new onset or worsening of adverse effects due to an expectation of harm associated with the treatment. Statins face reputational challenges due to a vast amount of negative attention on the internet. We need to address the nocebo effect by managing the perception of statins and provide patients with objective information about statin treatment, reduce the negative expectations, and placing discussion about the likelihood of adverse effects into the context of treatment benefit.

Association between renal sympathetic denervation and arterial stiffness: the ASORAS study.

OBJECTIVES: Renal sympathetic denervation (RDN) reduces blood pressure (BP). However, one out of three patients does not exhibit a significant BP response to the therapy. This study investigates the association between noninvasive vascular stiffness indices and RDN-mediated BP reduction. METHODS: In this prospective, single-arm pilot study, patients with systolic office BP at least 140 mmHg, mean 24-h systolic ambulatory blood pressure (ABP) at least 130 mmHg and at least three prescribed antihypertensive drugs underwent radiofrequency RDN. The primary efficacy endpoint was temporal evolution of mean 24-h systolic ABP throughout 1-year post RDN (measured at baseline and 3-6-12 months). Effect modification was studied for baseline ultrasound carotid-femoral and magnetic resonance (MR) pulse wave velocity (PWV), MR aortic distensibility, cardiac MR left ventricular parameters and clinical variables. Statistical analyses were performed using linear mixed-effects models, and effect modification was assessed using interaction terms. RESULTS: Thirty patients (mean age 62.5 ±â€Š10.7 years, 50% women) with mean 24-h ABP 146.7/80.8 ±â€Š13.7/12.0 mmHg were enrolled. Following RDN, mean 24-h systolic ABP changed with -8.4 (95% CI: -14.5 to -2.3) mmHg/year ( P  = 0.007). Independent effect modifiers were CF-PWV [+2.7 (0.3 to 5.1) mmHg/year change in outcome for every m/s increase in CF-PWV; P  = 0.03], daytime diastolic ABP [-0.4 (-0.8 to 0.0) mmHg/year per mmHg; P  = 0.03], age [+0.6 (0.2 to 1.0) mmHg/year per year of age; P  = 0.006], female sex [-14.0 (-23.1 to -5.0) mmHg/year as compared with men; P  = 0.003] and BMI [+1.2 (0.1 to 2.2) mmHg/year per kg/m 2 ; P  = 0.04]. CONCLUSION: Higher CF-PWV at baseline was associated with a smaller reduction in systolic ABP following RDN. These findings could contribute to improve identification of RDN responders.

Monitoring antihypertensive drug concentrations to determine nonadherence in hypertensive patients with or without a kidney transplant.

BACKGROUND: Nonadherence to antihypertensive drugs (AHDs) is a major contributor to pseudo-resistant hypertension. The primary objective of this study was to determine the prevalence of nonadherence to AHDs among patients visiting the nephrology and vascular outpatient clinics. METHODS: Patients were eligible to participate in this prospective observational study if they used at least two AHDs that could be measured with a validated UHPLC-MS/MS method and had an office blood pressure at least 140 and/or at least 90 mmHg. For resistant hypertension, included patients had to use at least three AHDs including a diuretic or four AHDs. Adherence was assessed by measuring drug concentrations in blood. The complete absence of drug in blood was defined as nonadherence. A posthoc analysis was performed to determine the influence of a having a kidney transplant on the adherence rates. RESULTS: One hundred and forty-two patients were included of whom 66 patients fulfilled the definition of resistant hypertension. The overall adherence rate to AHDs was 78.2% ( n  = 111 patients), with the highest adherence rate for irbesartan (100%, n  = 9) and lowest adherence rate for bumetanide ( n  = 69%, n  = 13). In further analysis, only kidney transplantation could be identified as an important factor for adherence (adjusted odds ratio = 3.35; 95% confidence interval 1.23-9.09). A posthoc analysis showed that patients with a kidney transplant were more likely to be adherent to AHDs (non-KT cohort 64.0% vs. KT-cohort 85.7%, χ 2 (2) = 10.34, P  = 0.006). CONCLUSION: The adherence rate to AHDs in hypertensive patients was high (78.2%) and even higher after a kidney transplant (85.7%). Furthermore, patients after kidney transplant had a lower risk of being nonadherent to AHDs.

Ad26.COV2.S priming provided a solid immunological base for mRNA-based COVID-19 booster vaccination.

The emergence of novel SARS-CoV-2 variants led to the recommendation of booster vaccinations after Ad26.COV2.S priming. It was previously shown that heterologous booster vaccination induces high antibody levels, but how heterologous boosters affect other functional aspects of the immune response remained unknown. Here, we performed immunological profiling of Ad26.COV2.S-primed individuals before and after homologous or heterologous (mRNA-1273 or BNT162b2) booster. Booster vaccinations increased functional antibodies targeting ancestral SARS-CoV-2 and emerging variants. Especially heterologous booster vaccinations induced high levels of functional antibodies. In contrast, T-cell responses were similar in magnitude following homologous or heterologous booster vaccination and retained cross-reactivity towards variants. Booster vaccination led to a minimal expansion of SARS-CoV-2-specific T-cell clones and no increase in the breadth of the T-cell repertoire. In conclusion, we show that Ad26.COV2.S priming vaccination provided a solid immunological base for heterologous boosting, increasing humoral and cellular responses targeting emerging variants of concern.

Immunogenicity of bivalent omicron (BA.1) booster vaccination after different priming regimens in health-care workers in the Netherlands (SWITCH ON): results from the direct boost group of an open-label, multicentre, randomised controlled trial.

BACKGROUND: Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and omicron spike (S) protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We aimed to assess the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent omicron (BA.1) vaccines in individuals who were primed with adenovirus-based or mRNA-based vaccines encoding the ancestral spike protein. METHODS: We analysed results of the direct boost group of the SWITCH ON study, an open-label, multicentre, randomised controlled trial. Health-care workers from four academic hospitals in the Netherlands aged 18-65 years who had completed a primary COVID-19 vaccination regimen and received one booster of an mRNA-based vaccine, given no later than 3 months previously, were eligible. Participants were randomly assigned (1:1) using computer software in block sizes of 16 and 24 to receive an omicron BA.1 bivalent booster straight away (direct boost group) or a bivalent omicron BA.5 booster, postponed for 90 days (postponed boost group), stratified by priming regimen. The BNT162b2 OMI BA.1 boost was given to participants younger than 45 years, and the mRNA-1273.214 boost was given to participants 45 years or older, as per Dutch guidelines. The direct boost group, whose results are presented here, were divided into four subgroups for analysis: (1) Ad26.COV2.S (Johnson & Johnson) prime and BNT162b2 OMI BA.1 (BioNTech-Pfizer) boost (Ad/P), (2) mRNA-based prime and BNT162b2 OMI BA.1 boost (mRNA/P), (3) Ad26.COV2.S prime and mRNA-1273.214 (Moderna) boost (Ad/M), and (4) mRNA-based prime and mRNA-1273.214 boost (mRNA/M). The primary outcome was fold change in S protein S1 subunit-specific IgG antibodies before and 28 days after booster vaccination. The primary outcome and safety were assessed in all participants except those who withdrew, had a SARS-CoV-2 breakthrough infection, or had a missing blood sample at day 0 or day 28. This trial is registered with ClinicalTrials.gov, NCT05471440. FINDINGS: Between Sept 2 and Oct 4, 2022, 219 (50%) of 434 eligible participants were randomly assigned to the direct boost group; 187 participants were included in the primary analyses; exclusions were mainly due to SARS-CoV-2 infection between days 0 and 28. From the 187 included participants, 138 (74%) were female and 49 (26%) were male. 42 (22%) of 187 participants received Ad/P and 44 (24%) mRNA/P (those aged <45 years), and 45 (24%) had received Ad/M and 56 (30%) mRNA/M (those aged ≥45 years). S1-specific binding antibody concentrations increased 7 days after bivalent booster vaccination and remained stable over 28 days in all four subgroups (geometric mean ratio [GMR] between day 0 and day 28 was 1·15 [95% CI 1·12-1·19] for the Ad/P group, 1·17 [1·14-1·20] for the mRNA/P group, 1·20 [1·17-1·23] for the Ad/M group, and 1·16 [1·13-1·19] for the mRNA/M group). We observed no significant difference in the GMR between the Ad/P and mRNA/P groups (p=0·51). The GMR appeared to be higher in the Ad/M group than in the mRNA/M group, but was not significant (p=0·073). Most side-effects were mild to moderate in severity and resolved within 48 h in most individuals. INTERPRETATION: Booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 in adult healthcare workers resulted in a rapid recall of humoral and cellular immune responses independent of the priming regimen. Monitoring of SARS-CoV-2 immunity at the population level, and simultaneously antigenic drift at the virus level, remains crucial to assess the necessity and timing of COVID-19 variant-specific booster vaccinations. FUNDING: The Netherlands Organization for Health Research and Development (ZonMw).

Adequacy of blood pressure control in high-risk hypertensive patients: The DEGREE study.

INTRODUCTION: Hypertension is a modifiable risk factor in patients at the highest risk for cardiovascular events. New invasive treatment options are becoming available that might be particularly appealing for high-risk patients. Therefore, the aim of this study was to determine the prevalence of high-risk patients on routine therapy that do not meet guideline recommended ambulatory blood pressure (ABP) targets. METHODS: This single-center, cross-sectional study was conducted at the Erasmus University Medical Center (Rotterdam, The Netherlands). Inclusion criteria were: (1) age 18-80 years, (2) drugs prescribed for hypertension or history of hypertension and (3) high cardiovascular risk as defined according to the European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines. Patients underwent standardized office blood pressure (OBP) and same-day 24-h ABP measurements. Blood pressure (BP) control was defined according to the 2018 ESC/ESH and 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. RESULTS: A total of 100 patients were enrolled (median age 71 years, 35% female). Mean OBP was 142.2/81.9 ± 18.6/12.6 mmHg and mean 24-h ABP was 126.1/70.1 ± 14.3/9.2 mmHg. Patients were on 2.0 [25th-75th percentile: 1.0-3.3] Defined Daily Doses of antihypertensive drugs. ESC/ESH guideline 24-h ABP and OBP targets were not met in 41.8% (95%CI: 31.5-52.6%) and 52.7% (95%CI: 42.0-63.3%), respectively. ACC/AHA guideline 24-h ABP and OBP targets were not met in 59.3% (95%CI: 48.5-69.5%) and 79.1% (95%CI: 69.3-86.9%), respectively. CONCLUSIONS: BP remains uncontrolled in 40-60% of high-risk hypertensive patients despite routine use of guideline-recommended therapy. Our findings support the search towards novel invasive BP lowering treatment options.

Analyzing the immunogenicity of bivalent booster vaccinations in healthcare workers: The SWITCH ON trial protocol.

Vaccination against coronavirus disease 2019 (COVID-19) has contributed greatly to providing protection against severe disease, thereby reducing hospital admissions and deaths. Several studies have reported reduction in vaccine effectiveness over time against the Omicron sub-lineages. However, the willingness to receive regular booster doses in the general population is declining. To determine the need for repeated booster vaccinations in healthy individuals and to aid policymakers in future public health interventions for COVID-19, we aim to gain insight into the immunogenicity of the additional bivalent booster vaccination in a representative sample of the healthy Dutch population. The SWITCH ON study was initiated to investigate three main topics: i) immunogenicity of bivalent vaccines after priming with adenovirus- or mRNA-based vaccines, ii) immunological recall responses and reactivity with relevant variants after booster vaccination, and iii) the necessity of booster vaccinations for the healthy population in the future. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT05471440.

Association between Clinical Frailty Scale score and hospital mortality in adult patients with COVID-19 (COMET): an international, multicentre, retrospective, observational cohort study.

BACKGROUND: During the COVID-19 pandemic, the scarcity of resources has necessitated triage of critical care for patients with the disease. In patients aged 65 years and older, triage decisions are regularly based on degree of frailty measured by the Clinical Frailty Scale (CFS). However, the CFS could also be useful in patients younger than 65 years. We aimed to examine the association between CFS score and hospital mortality and between CFS score and admission to intensive care in adult patients of all ages with COVID-19 across Europe. METHODS: This analysis was part of the COVID Medication (COMET) study, an international, multicentre, retrospective observational cohort study in 63 hospitals in 11 countries in Europe. Eligible patients were aged 18 years and older, had been admitted to hospital, and either tested positive by PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or were judged to have a high clinical likelihood of having SARS-CoV-2 infection by the local COVID-19 expert team. CFS was used to assess level of frailty: fit (CFS1-3), mildly frail (CFS4-5), or frail (CFS6-9). The primary outcome was hospital mortality. The secondary outcome was admission to intensive care. Data were analysed using a multivariable binary logistic regression model adjusted for covariates (age, sex, number of drugs prescribed, and type of drug class as a proxy for comorbidities). FINDINGS: Between March 30 and July 15, 2020, 2434 patients (median age 68 years [IQR 55-77]; 1480 [61%] men, 954 [30%] women) had CFS scores available and were included in the analyses. In the total sample and in patients aged 65 years and older, frail patients and mildly frail patients had a significantly higher risk of hospital mortality than fit patients (total sample: CFS6-9 vs CFS1-3 odds ratio [OR] 2·71 [95% CI 2·04-3·60], p<0·0001 and CFS4-5 vs CFS1-3 OR 1·54 [1·16-2·06], p=0·0030; age ≥65 years: CFS6-9 vs CFS1-3 OR 2·90 [2·12-3·97], p<0·0001 and CFS4-5 vs CFS1-3 OR 1·64 [1·20-2·25], p=0·0020). In patients younger than 65 years, an increased hospital mortality risk was only observed in frail patients (CFS6-9 vs CFS1-3 OR 2·22 [1·08-4·57], p=0·030; CFS4-5 vs CFS1-3 OR 1·08 [0·48-2·39], p=0·86). Frail patients had a higher incidence of admission to intensive care than fit patients (CFS6-9 vs CFS1-3 OR 1·54 [1·21-1·97], p=0·0010), whereas mildly frail patients had a lower incidence than fit patients (CFS4-5 vs CFS1-3 OR 0·71 [0·55-0·92], p=0·0090). Among patients younger than 65 years, frail patients had an increased incidence of admission to intensive care (CFS6-9 vs CFS1-3 OR 2·96 [1·98-4·43], p<0·0001), whereas mildly frail patients had no significant difference in incidence compared with fit patients (CFS4-5 vs CFS1-3 OR 0·93 [0·63-1·38], p=0·72). Among patients aged 65 years and older, frail patients had no significant difference in the incidence of admission to intensive care compared with fit patients (CFS6-9 vs CFS1-3 OR 1·27 [0·92-1·75], p=0·14), whereas mildly frail patients had a lower incidence than fit patients (CFS4-5 vs CFS1-3 OR 0·66 [0·47-0·93], p=0·018). INTERPRETATION: The results of this study suggest that CFS score is a suitable risk marker for hospital mortality in adult patients with COVID-19. However, treatment decisions based on the CFS in patients younger than 65 years should be made with caution. FUNDING: LOEY Foundation.

[Medicines: what has the last decade given us and what can we expect in the coming 10 years?] / Geneesmiddelen: 10 jaar terug en vooruitkijken.

Recent years have seen important changes in pharmacology. New techniques have been developed which are increasingly aimed at smaller groups of patients or even individual patients. In the past, thousands of chemical molecules were tested on a potential molecular target and the most effective molecules were selected. Nowadays a growing number of drugs are designed to aim at a specific molecular target, an example being monoclonal antibodies. There are developments that go fundamentally further and enable patients to be treated in an increasingly targeted and individual manner. These new therapies (i.e., Advanced Therapy Medicinal Products) are based on different principles than those of classical pharmacotherapy, and require different risk assessments as well as a different regulatory system. In this paper we discuss a selection of the developments in pharmacotherapy that have taken place during the past decade. In addition, we look into what sort of developments can be expected in the future.

COvid MEdicaTion (COMET) study: protocol for a cohort study.

Various theories about drugs such as ACE inhibitors or angiotensin II receptor blockers (ARBs) in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical outcomes of COVID-19 are circulating in both mainstream media and medical literature. These are based on the fact that ACE2 facilitates SARS-CoV-2 cell invasion via binding of a viral spike protein to ACE2. However, the effect of ACE inhibitors, ARBs and other drugs on ACE2 is unclear and all theories are based on conflicting evidence mainly from animal studies. Therefore, clinical evidence is urgently needed. The aim of this study is to investigate the relationship between use of these drugs on clinical outcome of patients with COVID-19. Patients will be included from several hospitals in Europe. Data will be collected in a user-friendly database (Digitalis) on an external server. Analyses will be adjusted for sex, age and presence of cardiovascular disease, hypertension and diabetes. These results will enable more rational choices for randomised controlled trials for preventive and therapeutic strategies in COVID-19.

[The polypill for cardiovascular disease: why is it used so infrequently?] / De polypil bij hart- en vaatziekte.

Cardiovascular polypills or fixed-dose combination (FDC) therapy have been advocated to improve treatment and prevention of cardiovascular disease since 2003. Yet, it is still used infrequently in current practice. This is in contrast to the widespread use of fixed-dose drug combinations for HIV, tuberculosis, and malaria worldwide. Over the past 15 years, evidence from studies in patients with elevated cardiovascular risk or manifest cardiovascular disease has become available, showing that FDC therapy is a strategy which improves adherence, lowers risk factor levels better than usual care, improves adherence to treatment goals, considerably lowers daily intake of pills, and simplifies drug regimens. Furthermore, patients uniformly indicate that this type of therapy is preferred over prescription of individual pills. Also, FDC therapy is reimbursed. Yet, in the Netherlands, only a small percentage of patients is prescribed a fixed dose combination pill. This raises the question what the underlying barriers are to adoption in clinical practice: is it availability, willingness, awareness, or a combination of factors?

Combined use of polypill components in patients with type 2 diabetes mellitus.

Objectives A polypill containing aspirin, a statin and blood pressure (BP)-lowering agents has been proposed for the prevention of cardiovascular disease. To increase adherence and reduce the gaps between indicated and used therapy, a polypill might be of interest for patients with type 2 diabetes (T2DM). Our aim was to assess the prevalence of the combined use of polypill components in patients with T2DM over time. Methods The combined use of polypill components was assessed between 1996 and 2015 in patients with T2DM in the prospective SMART cohort ( n = 1828). The results were dichotomized into patients without ( n = 568) and with ( n = 1260) vascular disease. The patient characteristics associated with the use of polypill components were evaluated. Results In total, 19% of patients with T2DM without vascular disease received a statin and ≥2 BP-lowering agents ('cardiovascular polypill') and 13% received additional oral glucose-lowering therapy ('diabetic polypill'). Of the patients with T2DM with vascular disease, 42% received the combination of an antiplatelet agent, a statin and ≥2 BP-lowering agents ('cardiovascular polypill') and 30% received additional glucose-lowering therapy ('diabetic polypill'). The prevalence of the use of the cardiovascular and diabetic polypill combination has substantially increased between 1996 and 2015 to 36 and 32% in patients without vascular disease and to 67 and 57% in patients with vascular disease. Conclusions Patients with T2DM frequently use polypill components, often together with oral glucose-lowering agents, and this rate of use has increased steadily between 1996 and 2015. Introducing a cardiovascular or diabetic polypill for patients with T2DM seems to be highly relevant.