Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

Survival After Invasive or Conservative Management of Stable Coronary Disease.

Background: The ISCHEMIA trial compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes over a median of 3.2 years. Extended follow-up for mortality is ongoing. Methods: ISCHEMIA participants were randomized to an initial invasive strategy (INV) added to guideline-directed medical therapy or a conservative strategy (CON). Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and non-cardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models and Bayesian methods. Undetermined deaths were classified as cardiovascular as pre-specified in the trial protocol. Results: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23 % women, 16% Hispanic, 4% Black, 42% diabetes, and median EF 0.60. A total of 557 deaths accrued over a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 non-cardiovascular deaths and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate 12.7% in INV, 13.4% in CON; adjusted hazard ratio (HR)=1.00, 95% CI: 0.85-1.18). There was a lower 7-year rate cardiovascular mortality (6.4% vs. 8.6%, adjusted HR=0.78, 95% CI: 0.63-0.96) with an initial invasive strategy but a higher 7-year rate of non-cardiovascular mortality (5.6% vs. 4.4%, adjusted HR=1.44, 95% CI: 1.08-1.91) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. Conclusions: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of non-cardiovascular mortality with an initial invasive strategy over a median follow-up of 5.7 years. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04894877; https://clinicaltrials.gov/ct2/show/NCT04894877.

Organ donation rates during the COVID-19 pandemic: Comparing the approach taken during the first two waves

Introduction: In response to the COVID-19 pandemic the many UK transplant units had to close or reduce activity, with deceased donation and transplantation down 80% in March-May 2020. Donor age criteria were reduced in the first wave to protect ICU capacity, and donation after brain death (DBD) was prioritised over donation after cardiac death (DCD). From June onwards, an NHSBT recovery plan aimed to reopen programmes, with the aim to return to a position of exploring all eligible donors and reviewing their potential on a case-by-case basis,1 but the ability of such programmes was impacted by a further rise in COVID-19 cases (second wave). Objectives: We aimed to compare the performance of NHSBT referral, donation, and transplantation strategies during the first two waves of COVID-19. Wave one was defined as 11/3/20 to 10/8/20, and wave two 11/8/20 to 10/3/21. Methods: Mortality and transplant data were acquired from the Potential Donor Audit (PDA) and national transplant registries. COVID-19 healthcare utilisation data was acquired via the PHE API. Correlation between features were assessed using Pearson's product-moment correlation coefficient and means compared using Student's t-test. Results: Weekly referral rates during the first wave were strongly inversely correlated to COVID-19 critical care utilisation (r=-0.82, 95%CI -.93 to -0.60) but moderately positively correlated during the second (r=0.61, 95%CI 0.31 to 0.80). Total transplanted organs were inversely correlated throughout (r=-0.64, 95%CI -0.78 to -0.44) with no difference between waves (p=0.055), although renal transplants were less effected during the second wave (p<0.001). The mean transplant gap (difference between organs retrieved and transplanted) was significantly higher in the second wave (5.9 per week, 95%CI 3.4 to 8.5, p<0.001). The DBD/DCD ratio was significantly lower in the second wave (reduced from 3.3 to 2.0, 95%CI for reduction 0.5-2.1, p=0.001). Conclusion: Referral rates to NHSBT improved during the second wave, and the ratio of DBD to DCD fell, both reflecting positively on the change of approach taken. Although total organ transplants fell during both waves, this is strongly correlated to critical care utilisation by COVID-19 patients, suggesting an impact on the ability for transplant centres to access critical care resources post-operatively. The relative sparing of renal transplants (who rarely require critical care post-operatively) and increasing transplant gap in the second wave fits with this assessment, although concerns regarding risks of COVID-19 in transplant recipients -especially in renal patients2-during periods of high burden of disease in hospital likely also contributed to reduced transplant rates,3 and the higher transplant gap could additionally be associated with the increase in DCD donation during the second wave.4.

Cause of death and consent rates during the COVID-19 pandemic

Introduction: The COVID-19 pandemic of 2020-21 impacted all aspects of the UK health service. Organ donation acceptance criteria were initially revised to safeguard critical care resources, and prioritised younger donors and donation after brain death (DBD) over donation after circulatory death (DCD).1 These were later returned to the original criteria prior to the second wave in September 2020;yet referrals and donation numbers remained below pre-pandemic levels throughout 2020. This data was further confounded by England changing from an opt-in model to presumed consent for donation.2 Objectives: We aimed to assess the impact of the COVID-19 pandemic on causes of death, and the subsequent effect on numbers of potential donors, referral rates (adjusted for the altered referral criteria during the first wave), and consent rates for donation. Methods: Mortality, referral, and consent rate data were acquired from the Potential Donor Audit (PDA) database held by NHS Blood and Transplant. The two pandemic waves (defined as 11/3/2020-10/08/2020 and 11/08/2020-10/03/2021) were compared to their corresponding periods from 2019-20. Event counts were compared using exact Poisson tests, and proportions using two-sample z-tests. Results: All-cause mortality was higher during both waves (p<0.001) than the previous year, with excess in-ICU non-COVID-19 mortality during the second wave (p=0.024, see figure). Mortality from cardiac arrest (p<0.001), catastrophic brain injury (p<0.001), and head trauma (p=0.280) were reduced in both waves, and deaths in ICU from suicide and self-harm were reduced in the second wave (p=0.002). After accounting for COVID-19 positive patients and those outside of the adjusted age-criteria, there was no difference in referral rates for potential DBD patients (99% in all cases) but fewer DCD patients meeting criteria were referred during both waves (89% vs 93%, p=0.003, and 85% vs 92%, p<0.001). There were fewer eligible donors during both waves (p<0.001). Fewer eligible families were approached during the first wave (42% vs 58%, p<0.001) but more were approached during the second (58% vs 54%, p=0.001) than in the preceding twelve months. There was no significant difference in Specialist Nurse in Organ Donation (SNOD) presence during approaches, nor family consent rates. Additionally, there was no difference in the proportion of patients who subsequently went on to donate. Conclusions: The reduction in donations - and hence transplantation - during the COVID-19 pandemic was multifactorial. There was a significant reduction in causes of mortality that aremost associated with donation, likely driven by an increased number of deaths in the community who never 'made it' to hospital. Potential DCDs were referred less frequently during both waves, although this was secondary to the change in acceptance criteria during the first wave. Additionally, fewer eligible families were approached during the first wave, further reducing donation potential. Despite fewer eligible donors, consent rates, the relationship between SNOD presence and consent, and progression to donation remained unchanged, suggesting that the foundations underpinning the organ donation programme remained resilient. Future work should focus on validating factors predicting family consent3 in the context of COVID-19 and assessing the ongoing impact of presumed consent.

The impact of COVID-19 on organ donation and transplantation in the UK: lessons learned from the first year of the pandemic.

The COVID-19 pandemic had a major impact on UK deceased organ donation and transplantation activity. We used national audit data from NHS Blood and Transplant to explore in detail the effects of the pandemic in comparison with 12 months pre-pandemic, and to consider the impact of the mitigating strategies and challenges placed on ICU by 'waves' of patients with COVID-19. Between 11 March 2020 and 10 March 2021, referrals to NHS Blood and Transplant of potential organ donors were initially inversely related to the number of people with COVID-19 undergoing mechanical ventilation in intensive care (incident rate ratio (95%CI) per 1000 patients 0.93 (0.88-0.99), p = 0.018), although this pattern reversed during the second wave (additional incident rate ratio (95%CI) 1.12 (1.05-1.19), p < 0.001). Adjusted numbers of donors (incident rate ratio (95%CI) 0.71 (0.61-0.81), p < 0.001) and organs retrieved (incident rate ratio (95%CI) 0.89 (0.82-0.97), p = 0.007) were inversely dependent on COVID-19 workload, though weekly numbers of transplants were unrelated (incident rate ratio (95%CI) 0.95 (0.86-1.04), p = 0.235). Non-COVID-19 mortality fell from 15,007 to 14,087 during the first wave (rate ratio (95%CI) 0.94 (0.92-0.96), p < 0.001) but climbed from 18,907 to 19,372 during the second wave (rate ratio (95%CI) 1.02 (1.00-1.05), p = 0.018). There were fewer in-hospital deaths from cardiac arrest and intracranial catastrophes throughout (rate ratio (95%CI) 0.83 (0.81-0.86), p < 0.001 and rate ratio (95%CI) 0.88 (0.85-0.91), p < 0.001, respectively). There were overall fewer eligible donors (n = 4282) when compared with pre-pandemic levels (n = 6038); OR (95%CI) 0.58 (0.51-0.66), p < 0.001. The total number of donations during the year fell from 1620 to 1140 (rate ratio (95%CI) 0.70 (0.65-0.76), p < 0.001), but the proportion of eligible donors who proceeded to donation (27%) was unchanged (OR (95%CI) 0.99 (0.91-1.08), p = 0.821). The reduction in donations and transplantation during the pandemic was multifactorial, but these data highlight the impact in the UK of a fall in eligible donors and an inverse relationship of referrals to COVID-19 workload. Despite the challenges faced, the foundations underpinning the UK deceased organ donation programme remained strong.

The impact of a national COVID-19 lockdown on acute coronary syndrome hospitalisations in New Zealand (ANZACS-QI 55).

BACKGROUND: Countries with a high incidence of coronavirus 2019 (COVID-19) reported reduced hospitalisations for acute coronary syndromes (ACS) during the pandemic. This study describes the impact of a nationwide lockdown on ACS hospitalisations in New Zealand (NZ), a country with a low incidence of COVID-19. METHODS: All patients admitted to a NZ Hospital with ACS who underwent coronary angiography in the All NZ ACS Quality Improvement registry during the lockdown (23 March - 26 April 2020) were compared with equivalent weeks in 2015-2019. Ambulance attendances and regional community troponin-I testing were compared for lockdown and non-lockdown (1 July 2019 to 16 February 2020) periods. FINDINGS: Hospitalisation for ACS was lower during the 5-week lockdown (105 vs. 146 per-week, rate ratio 0•72 [95% CI 0•61-0•83], p = 0.003). This was explained by fewer admissions for non-ST-segment elevation ACS (NSTE-ACS; p = 0•002) but not ST-segment elevation myocardial infarction (STEMI; p = 0•31). Patient characteristics and in-hospital mortality were similar. For STEMI, door-to-balloon times were similar (70 vs. 72 min, p = 0•52). For NSTE-ACS, there was an increase in percutaneous revascularisation (59% vs. 49%, p<0•001) and reduction in surgical revascularisation (9% vs. 15%, p = 0•005). There were fewer ambulance attendances for cardiac arrests (98 vs. 110 per-week, p = 0•04) but no difference for suspected ACS (408 vs. 420 per-week, p = 0•44). Community troponin testing was lower throughout the lockdown (182 vs. 394 per-week, p<0•001). INTERPRETATION: Despite the low incidence of COVID-19, there was a nationwide decrease in ACS hospitalisations during the lockdown. These findings have important implications for future pandemic planning. FUNDING: The ANZACS-QI registry receives funding from the New Zealand Ministry of Health.

Assessing whether COVID-19 patients will benefit from critical care, and an objective approach to capacity challenges during a pandemic: An Intensive Care Society clinical guideline.

This national professional society guidance lays out operational and ethical principles for decision-making during a pandemic, in the immediate context of COVID-19 in the early 2020 surge iteration but with potential ongoing relevance. It identifies the different phases of a pandemic and the implications for capacity and mutual aid within a national healthcare system, and introduces a revised CRITCON-PANDEMIC framework for shared operational responsibilities and clinical decision-making. Usual legal and ethical frameworks should continue to apply while capacity and mutual aid are available (CRITCON-PANDEMIC levels 0-3); clinicians should focus on current clinical needs and should not treat patients differently because of anticipated future pressures. In conditions of resource limitation (CRITCON-PANDEMIC 4), a structured and equitable approach is necessary and an objective Decision Support Aid is proposed. In producing this guidance, we emphasise that all patients must be treated with respect and without discrimination, because everyone is of equal value. The guidance has been put together with input from patient and public groups and aims to provide standards that are fair to everyone. We acknowledge that COVID-19 is a new disease with a partial and evolving knowledge base, and aim to provide an objective clinical decision-making framework based on the best available information. It is recognised that a factual assessment of likely benefit may take into account age, frailty and comorbidities, but the guidance emphasises that every assessment must be individualised on a balanced, case by case, basis and may inform clinical judgement but not replace it. The effects of a comorbidity on someone's ability to benefit from critical care should be individually assessed. Measures of frailty should be used with care, and should not disadvantage those with stable disability.