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Introduction: Secondary prevention of cardiovascular events among patients with diagnosed cardiovascular disease and high ischemic risk poses a significant challenge in clinical practice. The combinations of aspirin with low dose (LD) Ticagrelor or LD-Rivaroxaban have shown superiority in preventing major adverse cardiovascular events (MACE) than aspirin treatment alone. The comparative value for money of these two regimens remains unexplored.Methods: We analyzed each regimen's annual cost needed to treat (CNT) by multiplying the annualized number needed to treat (aNNT) by the annual cost of each drug. The aNNTs were based on outcome data from PEGASUS TIMI-54 and COMPASS trials. Scenario analyses were performed to overcome variances in terms of population risk. Costs were based on 2021 US prices. The primary outcome was defined as CNT to prevent one MACE across the two regimens. Secondary value analysis was performed for myocardial infarction (MI), stroke, and CV death as separate outcomes. Results: The aNNTs to prevent MACE with LD-Ticagrelor and with LD-Rivaroxaban were 229 [95% confidence interval (CI):141-734] and 147 (95%CI:104-252), respectively. At an annual cost of 3,618$ versus 4,308$, the corresponding CNTs were 828,478$ (95%CI:510,111$-2,655,471$) with LD-Ticagrelor and 633,270$ (95%CI:448,028$-1,085,607$) with LD-Rivaroxaban. LD-Rivaroxaban.Conclusion: Combining aspirin with LD-Rivaroxaban provides better value for money than with LD-Ticagrelor for secondary prevention of MACE.

BackgroundData suggest that vaccine effectiveness against Covid-19-associated hospital admission and mortality is augmented with booster doses, but the benefit wanes within several months. However, the CDC recently concluded that second doses of bivalent vaccines this Spring were not warranted because existing data were insufficient to analyze the benefits of such a strategy. Therefore, our objective was to assess whether routinely boosting high-risk populations at least every 6 months may be warranted, depending on age and immune status.MethodsUtilizing a database of 3,574,243 members of Clalit Health Services (CHS), we analyzed the medical records of individuals who received none, or at least one dose of the BNT162b2 mRNA COVID-19 vaccine between January 1, 2021, and April 5, 2022. We examined the risk of moderate-to-severe Covid-19 hospitalization or death stratified by age group, immune status and time since receipt of the last vaccine dose during the early Omicron wave in Israel (December 20, 2021 to April 5, 2022). The number needed to vaccinate (NNV) was calculated as the inverse of the absolute risk reduction for various subgroups and Covid-19 waves.ResultsEligibility criteria were met by 3,381,480 CHS members. The absolute risk of Covid-19 moderate-to severe hospitalization or death during the Omicron wave increased with age, immunocompromised status, and time since receipt of the last vaccine dose. The NNVs varied greatly by age and immune status and were contingent on various disease prevalence scenarios. Among the severely immunocompromised, boosting at the start of the Omicron wave had an NNV ranging from 87 (95% CI 70-109) in persons ages ≥80 to 1,037 (95% CI 999 -1,513) in persons ages 12-59. In the lower prevalence periods, the NNV for 6-month booster cadencing remained favorable for immunocompromised people in all age groups and immunocompetent people ages ≥60.ConclusionsOur study provides evidence for the potential benefit of a routine 6-month cadence for Covid-19 boosters for the highest-risk groups, and possibly more frequently, even during relatively lower Covid-19 prevalence.

Empagliflozin and oral semaglutide reduce the incidence of cardiovascular mortality (CVM) in patients with type 2 diabetes mellitus. However, these therapies impose a significant financial burden on healthcare systems. Therefore, we compared the value for money of empagliflozin versus oral semaglutide to prevent CVM. We calculated the cost needed to treat to prevent 1 case of CVM using either drug by multiplying the annualized number needed to treat to prevent 1 event by the annual cost of the therapy. Efficacy estimates were extracted from published randomized controlled trials data. We performed a scenario analysis to mitigate the primary differences between the populations of randomized controlled trials. Drug costs were calculated as 75% of the United States National Average Drug Acquisition Cost listing. The annualized number needed to treat for empagliflozin in EMPA-REG-OUTCOME was 141 (95% confidence interval [CI] 104 to 230) and 141 (95% CI 96 to 879) for oral semaglutide in PIONEER 6. The annual treatment costs are $4,797 for empagliflozin versus $7,133 for oral semaglutide. Therefore, the corresponding costs needed to treat are $676,385 ($498,894-$1,101,039) and $1,005,855 (95% CI $684,837-$6,270,544) respectively. In conclusion, our findings suggest that empagliflozin provides better value for money than oral semaglutide to prevent CVM in patients with type 2 diabetes mellitus at the current United States prices of the interventions.

The rapid emergence of the B.1.1.529 (Omicron) variant of SARS-CoV-2 led to a global resurgence of coronavirus disease 2019 (COVID-19). Israeli authorities approved a fourth COVID-19 vaccine dose (second booster) for individuals aged 60 years and over who had received a first booster dose 4 or more months earlier. Evidence for the effectiveness of a second booster dose in reducing hospitalizations and mortality due to COVID-19 is warranted. This retrospective cohort study included all members of Clalit Health Services who were aged 60-100 years and who were eligible for the second booster on 3 January 2022. Hospitalizations and mortality due to COVID-19 in participants who received the second booster were compared with those for participants who received one booster dose. Cox proportional hazards regression models with time-dependent covariates were used to estimate the association between the second booster and hospitalization and death due to COVID-19 while adjusting for demographic factors and coexisting illnesses. A total of 563,465 participants met the eligibility criteria. Of those, 328,597 (58%) received a second booster dose during the 40 day study period. Hospitalization due to COVID-19 occurred in 270 of the second-booster recipients and in 550 participants who received one booster dose (adjusted hazard ratio, 0.36; 95% confidence interval (CI): 0.31-0.43). Death due to COVID-19 occurred in 92 second-booster recipients and in 232 participants who received one booster dose (adjusted hazard ratio, 0.22; 95% CI: 0.17-0.28). This study demonstrates a substantial reduction in hospitalizations and deaths due to COVID-19 conferred by a second booster in Israeli adults aged 60 years and over.

The risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) decreases substantially among patients who have recovered from coronavirus disease 2019 (Covid-19). However, it is unknown how long protective immunity lasts. Current guidelines recommend vaccination of recovered patients even though data regarding vaccine effectiveness in such cases are still limited.In this retrospective cohort study, we reviewed electronic medical records from a large health care organization in Israel to assess reinfection rates in patients who had recovered from SARS-CoV-2 infection before any vaccination against Covid-19. We compared reinfection rates among patients who had subsequently received the BNT162b2 vaccine (Pfizer-BioNTech) and those who had not been vaccinated between March 1 and November 26, 2021. We used a Cox proportional-hazards regression model with time-dependent covariates to estimate the association between vaccination and reinfection after adjustment for demographic factors and coexisting illnesses. Vaccine effectiveness was estimated as 1 minus the hazard ratio. In a secondary analysis, we evaluated the vaccine effectiveness of one dose as compared with two doses.A total of 149,032 patients who had recovered from SARS-CoV-2 infection met the eligibility criteria. Of these patients, 83,356 (56%) received subsequent vaccination during the 270-day study period. Reinfection occurred in 354 of the vaccinated patients (2.46 cases per 100,000 persons per day) and in 2168 of 65,676 unvaccinated patients (10.21 cases per 100,000 persons per day). Vaccine effectiveness was estimated at 82% (95% confidence interval [CI], 80 to 84) among patients who were 16 to 64 years of age and 60% (95% CI, 36 to 76) among those 65 years of age or older. No significant difference in vaccine effectiveness was found for one dose as compared with two doses.Among patients who had recovered from Covid-19, the receipt of at least one dose of the BNT162b2 vaccine was associated with a significantly lower risk of recurrent infection.

Background : Israel began a mass vaccination program with the rapid rollout of the Pfizer-BioNTech COVID-19 BNT162b2 vaccine for adults. At the same time, government stringency measures in terms of closing public life were decreased. Our objective was to estimate the total number of Covid-19 deaths avoided due to the massive vaccination campaign in the elderly Israeli population. Methods : We examined the effect of vaccination on mortality when at least 90% of the population over age 70 were vaccinated for less than seven months. Projected deaths as expected from vaccine efficacy and actual mortality data were compared for the study population to account for potential confounding effects of government stringency. The average Oxford Stringency Index was calculated in the study period and the preceding period of the pandemic. Potential confounding effects of an age shift in the distribution of deaths were examined by analyzing the distributions before and after the study period. Results : Confirmed deaths from COVID-19 in the population over 70 after mass vaccination were recorded as 370, versus 5,120 estimated without vaccinations. Conclusions : Vaccines against COVID-19 saved more lives than expected by simply applying individual vaccine efficacy to the vaccinated population in Israel, despite a loosening of government stringency. Our findings support the worldwide efforts of governments to improve vaccination rates, especially in the elderly population.

Higher doses of the glucagon-like peptide-1 agonist (GLP-1RA) semaglutide and, more recently, tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1RA demonstrated a significant reduction in body weight in patients with Type 2 Diabetes Mellitus (T2DM). However, their comparative value for money for this indication is unclear. Therefore, we aimed to establish which provides better value for money.We calculated the cost needed to treat (CNT) to achieve a one percent reduction in body weight using high-dose tirzepatide (15mg) versus semaglutide (2.4mg). The body weight reductions were extracted from published results of SURMOUNT-1 and STEP 1 trials, respectively. In addition, we performed a scenario analysis to mitigate the primary differences between the two studies' populations. Drug costs were based on US GoodRx prices as of October 2022.Using tirzepatide resulted in a weight loss of 17.8% (95% CI: 16.3%-19.3%) compared to 12.4% (95% CI: 11.5%-13.4%) for semaglutide. The total cost of 72 weeks of tirzepatide was estimated at $17,527 compared with $22,878 for 68 weeks of semaglutide. Accordingly, the CNT per one percent of body weight reduction with tirzepatide is estimated at $985 (95% CI:$908-$1,075) compared to $1,845 (95% CI: $1,707-$1,989) with semaglutide. Scenario analysis confirmed these findings.Tirzepatide provides better value for money than semaglutide for weight reduction. This article is protected by copyright. All rights reserved.

The recent global outbreak of the human monkeypox virus was declared a public health emergency by the WHO. Modified Vaccinia Ankara (MVA), provided in a two-dose regimen, is currently the only FDA-approved vaccine against monkeypox virus infection (MPXVi). Nevertheless, many have implemented a single-dose strategy to maximize vaccine supply because of a vaccine shortage. The emergency approval of MVA use for MPXVi was based only on efficacy data from non-human primates. Evidence for the real-life effectiveness of MVA in reducing MPXVi is still warranted. This observational, retrospective cohort study included all members of Clalit Health Services (CHS), eligible for the MVA vaccine on Jul. 31, 2022, when the CHS vaccination campaign was initiated. The rate of MPXVi in participants who received one dose of MVA was compared with that for participants who were not vaccinated. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between vaccination and MPXVi while adjusting for sociodemographic and clinical risk factors. A total of 2,092 subjects met vaccine eligibility criteria. Of those, 1,068 (51%) were vaccinated during the 105 days study period and completed at least 25 days of follow-up. During the study period, 5 infections were confirmed in the vaccinated and 16 infections were confirmed in the unvaccinated participants. The adjusted vaccine effectiveness was estimated at 87% (95% CI: 60%-95%). Our results suggest that a single dose of subcutaneous MVA is associated with a significantly lower risk for MPXVi in high-risk individuals and may contribute to the containment of the current outbreak.

Background The global supply of vaccines against monkeypox virus infection (MPXVi) is significantly lower than demand. Evidence-based vaccine prioritization criteria, based on risk assessment, are essential for fair vaccine distribution. Our objective was to identify the characteristics of individuals at the highest risk for MPXVi. Methods This population-based cohort study included all Clalit Health Services (CHS) subjects assumed to be at risk for MPXVi, based on known characteristics of infected subjects worldwide and insights of LGBTQ+ -specialized CHS clinicians. Cox hazards models were used to identify risk factors for MPXVi in the study cohort. The study commenced on June 6, 2022, the date of the first known MPXVi in CHS patients, until July 31, 2022, when the MPXV vaccination campaign started. Results 8,088 individuals (0.18% of the CHS total population) were identified according to the study inclusion criteria. Of those, 69 (0.85%) were infected during the study period. Risk factors for MPXVi were birth in 1980 or later, history of syphilis, HIV-PrEP use, PDE5 inhibitors use, recent STIs, and registeration to primary healthcare clinics in the Tel-Aviv district. No infections were observed in individuals with none of the factors. Individuals with 3+ risk factors had a 20-fold higher risk for MPXVi compared to those with 0-2, with 85.5% sensitivity and 77.8% specificity. Conclusions Counting the number of validated risk factors per individual seems to provide a robust, simple risk score for MPXVi. Weighting individuals’ risk levels against vaccine availability can assist health systems in the equitable prioritization of vaccine allocation.

Background The oral antiviral molnupiravir is moderately effective in high-risk, unvaccinated non-hospitalized patients infected with early variants of SARS-CoV-2. Data regarding the effectiveness of molnupiravir against the B.1.1.529 (omicron) variant and in vaccinated populations are limited. Methods We obtained data for all members of Clalit Health Services, 40 years of age and older, eligible for molnupiravir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between molnupiravir treatment and hospitalizations and deaths due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and prior Covid-19 immunity status. Results A total of 19,868 participants met the eligibility criteria, of whom 1,069 (5%) received molnupiravir during the study period. In patients 65 years and above, the rate of hospitalizations related to Covid-19 in treated compared to untreated patients was 74.6 versus 127.6 per 100,000 person-days; adjusted hazard ratio (HR) 0.55 (95% CI, 0.34 to 0.88). The adjusted HR for death due to Covid-19 was 0.26 (95% CI, 0.10 to 0.73). Among patients aged 40 to 64, the hospitalizations rate in treated compared to untreated patients was 125.8 versus 49.1 per 100,000 person-days; adjusted HR 1.80 (95% CI, 0.86 to 3.77). The adjusted HR for death was 12.8 (95% CI, 3.41 to 48.2). Conclusions In a cohort of non-hospitalized, omicron-infected high-risk patients, molnupiravir therapy was associated with a significant reduction in hospitalizations and mortality due to Covid-19 in patients 65 years and above. However, no evidence of benefit was found in younger adults.

Background The recent global outbreak of the human monkeypox virus (MPXV) was declared a public health emergency by the World Health Organization. Modified Vaccinia Ankara (MVA) is currently the only FDA-approved vaccine against MPXV that was approved for this indication based on a study in non-human primates. Since there is currently scarce evidence of the efficacy in humans, our objective was to evaluate real-life vaccine effectiveness (VE) after providing one vaccine dose to individuals at risk of MPVX infection. Methods The study cohort included all Clalit Health Services (CHS) members eligible for the MVA vaccine as defined by the Israeli Ministry of Health. The study commenced on July 31, 2022, when the MVA vaccination campaign was initiated in CHS, and participants were followed until September 12, 2022. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between vaccination and MPXV infections with adjustment for sociodemographic and clinical risk factors. Findings A total of 1,970 subjects met the study eligibility criteria (0.04% of CHS members). Of them, 873 (44%) were vaccinated with MVA and completed at least 25 days of follow-up. 18 infections were confirmed in CHS during the study period, 3 in vaccinated and 15 in unvaccinated status (40.0 versus 6.4 per 100,000 person days). VE was estimated at 79% (95% CI: 24%-94%). Interpretation Our results suggest that a single dose of MVA is associated with a significantly lower risk for MPVX infection in high-risk individuals. These findings highlight that urgent MVA vaccination of high-risk individuals may contribute to the containment of the current MPXV outbreak.

The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited.We obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status.A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75).Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.

BackgroundThe recent global outbreak of the human monkeypox virus (MPXV) was declared a public health emergency by the World Health Organization. Modified Vaccinia Ankara (MVA) is currently the only FDA-approved vaccine against MPXV that was approved for this indication based on a study in non-human primates. Since there is currently scarce evidence of the efficacy in humans, our objective was to evaluate real-life vaccine effectiveness (VE) after providing one vaccine dose to individuals at risk of MPVX infection.MethodsThe study cohort included all Clalit Health Services (CHS) members estimated to be at moderate to high risk for MPXV infection. The study commenced on July 31, 2022, when the MVA vaccination campaign was initiated in CHS, and participants were followed until August 10, 2022. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between vaccination and MPXV infections with adjustment for sociodemographic and clinical risk factors.Results8,168 subjects met the study eligibility criteria (0.17% of CHS members). Of them, 626 (7.7%) were vaccinated with MVA and completed at least 7 days of follow-up. 14 infections were confirmed in CHS during the study period, all within the study cohort and all in unvaccinated participants. VE was estimated at 100% (95% CI: 100%-100%).ConclusionsThese short-term preliminary results suggest a very high VE of a single dose of MVA for MPVX infection in moderate to high-risk individuals. These findings suggest that urgent MVA vaccination of high-risk subjects may contribute to outbreak containment.

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP1a), reduces the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus (T2DM). An oral version of semaglutide is now available, and patients may prefer it over the subcutaneous form. Our objective was to compare the value for money of the two modalities by assessing the cost needed to treat (CNT) to prevent MACE.The CNT to prevent MACE was figured by multiplying the one-year number needed to treat (NNT) with either oral or subcutaneous semaglutide by the annual cost of therapy. Efficacy estimates and the resulting NNT figures were extracted from the published results of the SUSTAIN-6 and the PIONEER-6 trials for the injectable and oral versions of semaglutide, respectively. Drug costs were estimated as 75% of the United States national average drug acquisition cost listing in June 2021. We performed a scenario analysis to mitigate the primary differences between the populations in the two trials. Sensitivity analysis was performed to evaluate the effect of price changes of the interventions.The CNT to prevent one MACE with subcutaneous semaglutide in SUSTAIN-6 was $966,693 ($594,888-$5,035,302) compared to $948,689 ($463,465-∞) with oral semaglutide in PIONEER-6. The scenario analysis demonstrated a 17% lower CNT for oral semaglutide. The difference between CNTs was sensitive to price fluctuations of the two interventions.Oral and subcutaneous semaglutide prescribed to prevent MACE in patients with T2DM provide similar value for money. The choice between both therapies should be guided mainly by patient preferences.

Aims The Angiotensin Receptor-Neprilysin Inhibitor sacubitril-valsartan (ARNI) and dapagliflozin, a sodium-glucose transport protein 2 inhibitor, reduce the risk of heart failure hospitalization (hHF) and cardiovascular (CV) mortality in patients with reduced ejection fraction (HFrEF). Their comparative value for money is undetermined. Therefore, our aim was to compare the cost per outcome implications of utilizing dapagliflozin vs. ARNI for preventing heart failure (HF) events of non-diabetic patients with HFrEF. Methods and results We calculated the cost needed to treat (CNT) to prevent one HF event. The cost needed to treat was estimated by multiplying the annualized number needed to treat (NNT) to prevent one event by each therapy’s annual cost. Efficacy estimates were extracted from published secondary analyses of non-diabetic patients in DAPA-HF and PARADIGM-HF trials. Drug costs were estimated as 75% of the 2020 US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed to mitigate differences between the trial’s populations and drug costs in various countries. The annualized NNT to prevent one HF event for dapagliflozin was 31 (95% CI 21–71) vs. 33 (95% CI 24–62) for ARNI. The CNT of dapagliflozin in the US is $141 112 (95% CI $95 592–$323 192) compared to $158 169 (95% CI $115 032–$297 166) for sacubitril-valsartan. The CNT results were sensitive to drug costs in various countries. Conclusion Dapagliflozin and ARNI provide comparable value for money for preventing HF events in non-diabetic patients with HFrEF. In healthcare settings where dapagliflozin’s price is significantly lower than ARNI, it provides superior value for money.

The rapid emergence of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus-2 led to a global resurgence of coronavirus disease 2019 (Covid-19). Israeli authorities approved a 4th Covid-19 vaccine dose (second-booster) for individuals aged 60 and above who received a first booster dose four or more months earlier. Evidence regarding the effectiveness of a second-booster dose in reducing mortality due to Covid-19 is warranted. This retrospective cohort study included all members of Clalit Health Services, aged 60 to 100, eligible for the second-booster. Mortality due to Covid-19 among participants who received the second-booster was compared with participants who received one booster dose. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between the second-booster and death due to Covid-19 while adjusting for demographic factors and coexisting illnesses. A total of 563,465 participants met the eligibility criteria. Of those, 328,597 (58%) received a second-booster dose during the 40-day study period. Death due to Covid-19 occurred in 92 second-booster recipients and in 232 participants who received one booster dose (adjusted hazard ratio 0.22; 95% confidence interval 0.17 to 0.28). This study demonstrates a substantial reduction in Covid-19 mortality by the second-booster in eligible subjects.

ObjectiveAtrial fibrillation (AF) screening by age achieves a low yield and misses younger individuals. We aimed to develop an algorithm in nationwide routinely collected primary care data to predict the risk of incident AF within 6 months (Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF)).MethodsWe used primary care electronic health record data from individuals aged ≥30 years without known AF in the UK Clinical Practice Research Datalink-GOLD dataset between 2 January 1998 and 30 November 2018, randomly divided into training (80%) and testing (20%) datasets. We trained a random forest classifier using age, sex, ethnicity and comorbidities. Prediction performance was evaluated in the testing dataset with internal bootstrap validation with 200 samples, and compared against the CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >75 (2 points), Stroke/transient ischaemic attack/thromboembolism (2 points), Vascular disease, Age 65–74, Sex category) and C2HEST (Coronary artery disease/Chronic obstructive pulmonary disease (1 point each), Hypertension, Elderly (age ≥75, 2 points), Systolic heart failure, Thyroid disease (hyperthyroidism)) scores. Cox proportional hazard models with competing risk of death were fit for incident longer-term AF between higher and lower FIND-AF-predicted risk.ResultsOf 2 081 139 individuals in the cohort, 7386 developed AF within 6 months. FIND-AF could be applied to all records. In the testing dataset (n=416 228), discrimination performance was strongest for FIND-AF (area under the receiver operating characteristic curve 0.824, 95% CI 0.814 to 0.834) compared with CHA2DS2-VASc (0.784, 0.773 to 0.794) and C2HEST (0.757, 0.744 to 0.770), and robust by sex and ethnic group. The higher predicted risk cohort, compared with lower predicted risk, had a 20-fold higher 6-month incidence rate for AF and higher long-term hazard for AF (HR 8.75, 95% CI 8.44 to 9.06).ConclusionsFIND-AF, a machine learning algorithm applicable at scale in routinely collected primary care data, identifies people at higher risk of short-term AF.

Background The emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 and the reduced effectiveness over time of the BNT162b2 vaccine (Pfizer–BioNTech) led to a resurgence of coronavirus disease 2019 (Covid-19) cases in populations that had been vaccinated early. On July 30, 2021, the Israeli Ministry of Health approved the use of a third dose of BNT162b2 (booster) to cope with this resurgence. Evidence regarding the effectiveness of the booster in lowering mortality due to Covid-19 is still needed. Methods We obtained data for all members of Clalit Health Services who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier. The mortality due to Covid-19 among participants who received the booster during the study period (booster group) was compared with that among participants who did not receive the booster (nonbooster group). A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of booster status with death due to Covid-19, with adjustment for sociodemographic factors and coexisting conditions. Results A total of 843,208 participants met the eligibility criteria, of whom 758,118 (90%) received the booster during the 54-day study period. Death due to Covid-19 occurred in 65 participants in the booster group (0.16 per 100,000 persons per day) and in 137 participants in the nonbooster group (2.98 per 100,000 persons per day). The adjusted hazard ratio for death due to Covid-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% confidence interval, 0.07 to 0.14; P

Introduction: Several innovative medications have recently demonstrated significant efficacy in preventing major adverse cardiovascular events. In many situations, payers need to understand promptly whether the novel interventions provide good value for their resources invested. Cost-effectiveness analysis (CEA) is the gold standard and cornerstone of pharmacoeconomic evaluation but requires significant resources, and is not always available at the period needed for reimbursement decisions. Therefore, we suggest using the "Cost Needed to Treat" (CNT) measure as a preliminary economic figure for comparing novel preventive therapies' value until valid CEA is available. CNT represents the extra cost of therapy needed to prevent one additional adverse event. The CNT is a product of the number needed to treat (NNT) and the cost of the therapy. A lower CNT indicates more value for money. To validate the usefulness of the CNT measure, we aimed to retrospectively compare outcomes of published CNT evaluations and the later published CEAs. Hypothesis: CNT measure and CEA result in comparable recommendations. Methods: We compared the conclusions of all published CNT evaluations with available published CEA results. Results: Seven published CNT figures, based on cardiovascular outcome trial results, were identified. Four CNTs had matched CEAs. The CNT evaluation and the CEA resulted in the same conclusions in all four cases (Figure 1). Conclusions: Outcomes of the published CNT evaluations seem to correlate with published CEA results. CNT seems to be a valuable, prompt tool for comparing novel preventive interventions' economic value.

Introduction: Patients with HF and reduced ejection fraction (HFrEF) are at high risk for CV mortality and HF-related hospitalizations (HHF). The Sodium-Glucose Transport protein 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin improve the outcomes of non-diabetic patients with HFrEF. We aimed to compare their value for money for this indication. Hypothesis: Empagliflozin and dapagliflozin have comparable value for money for improving the HF outcomes of non-diabetic patients with HFrEF. Methods: SGLT2i data was extracted from published results of empagliflozin and dapagliflozin in the subgroups of patients without diabetes. The primary clinical outcome measure was a composite of HHF or CV mortality events. The economic measure was the cost needed to treat (CNT) to prevent one event, calculated by multiplying the one-year number needed to treat (NNT) to prevent one event by the annual cost of each therapy. Drug costs were based on the 2021 US National Average Drug Acquisition Cost prices. Secondary outcomes were the CNT to prevent one event of HHF and CV mortality as separate clinical outcomes. Sensitivity analysis was performed to mitigate differences between the trial’s populations Results: Treatment with empagliflozin in EMPEROR-REDUCED has resulted in an NNT of 29 (95% CI: 18-212) compared to 32 (95% CI: 21-72) with dapagliflozin in DAPA-HF. Accordingly the CNT to prevent one event of CVM or HHF was $139,115 (95% CI: $86,347-$1,016,976) and $144,751 (95% CI: $94,993-$325,690), respectively. The sensitivity analysis confirmed the primary results, but the CNT to prevent CV mortality is significantly lower with dapagliflozin (Fig. 1) Conclusions: Empagliflozin and dapagliflozin have comparable value for money for improving HF outcomes of non-diabetic patients with HFrEF, with an advantage for dapagliflozin in CV mortality.

Introduction: Secondary prevention of cardiovascular events among patients with diagnosed cardiovascular disease and high ischemic risk poses a significant challenge in clinical practice. Both Ticagrelor and low-dose (LD) Rivaroxaban have shown superiority in preventing major adverse cardiovascular events (MACE) than aspirin treatment alone. The comparative value for money of these two regimens remains unexplored. Hypothesis: Ticagrelor and LD-Rivaroxaban are comparable in their clinical efficacy and cost-effectiveness. Methods: We analyzed the annualized cost needed to treat (CNT) of each regimen by multiplying the annualized number needed to treat (aNNT) by the annual cost of each drug. The aNNTs were based on outcome data from PEGASUS TIMI-54 and COMPASS trials. Scenario analyses were performed to overcome variances in terms of population risk. Costs were based on 2021 US prices. Secondary outcomes analysis was performed for myocardial infarction (MI), stroke, and CV death as separate outcomes. Results: The aNNTs to prevent MACE with Ticagrelor and with LD-Rivaroxaban were 207 [95% confidence interval (CI):138-553] and 147 (95%CI:104-252), respectively. At an annual cost of $3,541 versus $4,308, the corresponding CNTs were 734,429$ (95%CI:489,619$-1,958,478$) with ticagrelor and 633,003$ (95%CI:446,826$-1,085,149$) with LD-Rivaroxaban. Results of the scenario and secondary outcomes analysis are presented in Figure 1 . Conclusions: LD-Rivaroxaban provides better value for money than Ticagrelor for secondary prevention of MACE. Ticagrelor offers an advantage over LD-Rivaroxaban specifically to prevent MI and should be considered in cases where MI is the primary concern.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is associated with frequent hospitalizations and an increased risk of death. There are no therapies with certain benefits for the treatment of HFpEF. Spironolactone and Sacubitril/Valsartan have shown marginal significance benefits in HFpEF and are approved to treat this condition. We aimed to compare the value for money of these treatments. Hypothesis: Spironolactone provides better value for money than Sacubitril/Valsartan for preventing HF events in patients with HFpEF. Methods: We compared the cost needed to treat (CNT) to prevent the composite outcome of HF hospitalization and CV death with Spironolactone or Sacubitril/Valsartan. The CNT was estimated by multiplying the annualized number needed-to-treat (aNNT) by the annual cost of therapy. The aNNTs were calculated based on data from the TOP-CAT and PARAGON trials. Costs were based on 2021 US prices. Scenario analyses were performed to attenuate the differences in the studies’ populations. Subgroup analyses were performed for mildly reduced EF. Results: The aNNT to prevent the composite outcome with Sacubitril/Valsartan in PARAGON was 53 [95% CI:28-∞] versus 107 (95% CI:51-∞), with spironolactone in TOPCAT. At an annual cost of $5,100 versus $1,353, The corresponding CNTs were $270,273 (95% CI:142,786-∞) for Sacubitril/Valsartan and $144,773 (95% CI:69,004-∞) for spironolactone. Figure 1 illustrates the results of the scenario and subgroup analysis. Conclusion: Despite lower clinical efficacy, spironolactone provides better value for money than Sacubitril/Valsartan in preventing HF hospitalizations and cardiovascular death among patients with HFpEF.

BackgroundIn December 2020, Israel began a mass vaccination program with the rapid rollout of the Pfizer-BioNTech COVID-19 BNT162b2 vaccine for adults in Israel. The campaign vaccinated fewer people than necessary for herd immunity. However, at the same time, government stringency measures in terms of closing public life were decreased. Real-world observational data were used to examine the effect of mass vaccination on Covid-19 mortality.MethodsThe study period to examine the effect of vaccination on mortality was chosen to capture when at least 90% of the population over age 70 were vaccinated for less than seven months. Projected deaths as expected from vaccine efficacy and actual mortality data were compared for the study population with examination of potential confounding effects of government stringency. Average government stringency (Oxford Stringency Index) was calculated in the study period and the preceding period of the pandemic. Potential confounding effects of an age shift in the distribution of deaths were examined by analyzing the distributions of deaths and cases before and after the study period.ResultsConfirmed deaths from COVID-19 in the population over 70 after mass vaccination were recorded as 370, versus 408 expected from applying person-days of vaccine efficacy, and 5,120 estimated without vaccinations.ConclusionsVaccines against COVID-19 saved more lives than expected by simply applying individual vaccine efficacy to the vaccinated population in Israel, despite a loosening of government stringency.

Background Comorbid heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (DM) is associated with a very high risk of HF events. Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), and dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, improve HF outcomes in these patients, but their comparative value for money in this patient population has not yet been determined. Objective We aimed to compare the cost needed to treat (CNT) to avoid an HF event with each drug. Methods CNT was estimated by multiplying the annualized number needed to treat (NNT) to prevent one HF event by the annual cost of each therapy. HF events were defined as the first event of hospitalization for HF or cardiovascular mortality. Drug efficacy data were extracted from published secondary analyses of patients with DM in the DAPA-HF and PARADIGM-HF trials. Drug costs were estimated as 75% of the 2021 US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed on parameters that may have affected the CNT. Results The annualized NNT was 24 (95% confidence interval [CI] 16-54) for dapagliflozin and 57 (95% CI 31-433) for the ARNI. At an annual cost of $US4523 and 5099, respectively, the CNT was $US108,563 (95% CI 72,375-244,267) for dapagliflozin and $US290,671 (95% CI 158,084-2,208,079) for the ARNI. Conclusions Dapagliflozin seems to offer greater value for money than the ARNI for patients with HFrEF and DM. Our results provide support for contemporary guidelines advocating the use of dapagliflozin in these patients.

BackgroundIn 2021 a new variant of SARS-CoV-2, which came to be called the alpha variant, spread around the world. There were conflicting reports on this COVID-19 variant strain’s potentially increased lethality. In Israel, this strain became predominant in a very short time period.MethodsCOVID-19 mortality and case fatality rates were examined in Israel in terms of weekly and cumulative numbers.ResultsCOVID-19 case fatality rates in Israel rose quickly at the beginning of the pandemic and peaked in May 2020. The highest crude mortality came later in the second and third waves, but case the case fatality rates did not rise in 2021 with the increasing dominance of the alpha variant.ConclusionsBased on the results of examining case-fatality and mortality rates, we concluded that while the alpha variant of the virus raised mortality, in line with the fact that it is more infectious than wild-type, once this strain was caught by patients in Israel, it was not more likely to kill them than the original strain

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin, canagliflozin, and dapagliflozin reduce the risk of heart failure (HF) events in patients with diabetes mellitus (DM) at high risk for HF. Differences in HF outcomes between SGLT2i were demonstrated in a recent-published meta-analysis. Nevertheless, comparative cost-effectiveness analyses of SGLT2i provided for this indication have not been published yet. Therefore, we aimed to provide a preceding economic comparison of the costs required for improving HF outcomes by these three SGLT2i. The primary outcome was the cost needed to treat (CNT) to prevent one event of hospitalization for HF or cardiovascular mortality. CNT is calculated by multiplying the annualized number needed to treat to prevent one event by the annual cost of therapy. Clinical outcome data were extracted from pre-specified cohorts of HF-naive patients in the pivotal randomized controlled trials (RCTs). Costs of interventions were estimated as 75% of the US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed to mitigate differences between the RCT's populations. We figured the CNT for the primary prevention of HF events in DM patients to be $542,328 ($409,044-$905,412) for empagliflozin, $2,347,488 ($1,066,208-∞) for canagliflozin and $2,128,374 ($1,204,740-$48,140,518) for dapagliflozin. Sensitivity analysis confirmed the cost benefit of empagliflozin. Our findings suggest that between the available SGLT2i, the cost of primary prevention of HF in patients with DM at high risk for HF is lowest with empagliflozin. These findings may help choose an SGLT2i until head-to-head RCTs, and comprehensive cost-effective analyses for this indication are available.

Introduction: The Glucagon-Like Peptide-1 receptor agonists (GLP-1a) semaglutide, dulaglutide, and liraglutide reduce major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus ( T2DM) and established CVD. The American Diabetes Association currently recommends providing GLP-1a therapy to this patient population independently of glycaemic control. Despite proven clinical benefits, providing GLP-1a to all guideline eligible patients is a significant cost burden on healthcare systems. Therefore, it is imperative to compare the value for money of these agents. Hypothesis: The newly introduced GLP-1a Semaglutide may be cost-saving compared to dulaglutide and liraglutide for preventing MACE in patients with established CVD and T2DM. Methods: We calculated the cost needed to prevent one MACE, by multiplying the annualized number needed to treat to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published RCT data. We performed a sensitivity analysis to mitigate differences between trial populations and other uncertainties. Drug costs were based on published US prices. Results: The cost needed to prevent one MACE with semaglutide is $557,187 ($331,491-$2,194,483) compared to $1,179,360 ($732,888-$2,746,224) with liraglutide and $1,605,904 ($706,044-∞) for dulaglutide. Sensitivity analysis confirmed the advantage of semaglutide. Conclusions: Semaglutide prescribed for secondary prevention of MACE in patients with T2DM and established CVD seems to provide more value for money than dulaglutide and liraglutide for the same purpose.

Introduction: Icosapent ethyl is currently the only drug approved for the prevention of major adverse cardiovascular events (MACE) in patients with hypertriglyceridemia, who are already on statin therapy. The approved use is both for secondary prevention in patients with established cardiovascular disease (CVD) or primary prevention for patients with diabetes and multiple risk factors. Despite its’ proven clinical benefits, the addition of icosapent ethyl to patient’s current treatment regimens may impose a significant cost burden on healthcare systems. Hypothesis: Prioritizing icosapent ethyl therapy for patients with an established CVD may provide significantly more value for money than when prescribed as primary prevention. Methods: We performed an analysis of the cost required for icosapent ethyl per achieved outcome when prescribed either for primary or for secondary prevention of MACE. The cost needed to treat (CNT) to prevent one MACE in the REDUCE-IT trial was estimated by multiplying the annualized number needed to treat to prevent one event, by the annual cost of therapy. The market price of icosapent ethyl in the US was estimated as 75% of the US national average drug acquisition cost listing. Results: In the REDUCE-IT population, the figured CNT of Icosapent ethyl provided as primary prevention was $874,500 (95% CI: $349,800-∞) vs. $206,965 (95% CI: $160,325-$294,415) for secondary prevention; P Conclusions: The CNT for patients receiving the drug for primary prevention of MACE was four-fold higher than when provided as secondary prevention. Our findings suggest that icosapent ethyl therapy for patients with an established CVD provides significantly more value for money.

Introduction: Semaglutide, a subcutaneous Glucagon-Like Peptide-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus (T2DM). An oral version of semaglutide is now available, and patients may prefer it over a subcutaneous injection. The value for money of the oral version for the prevention of MACE is not clear. Hypothesis: Oral semaglutide provides less value for money than subcutaneous semaglutide for the prevention of MACE, but more value for money for the prevention of the single endpoint of cardiovascular mortality (CVM). Methods: We calculated the cost needed to prevent (CNT) one MACE, by multiplying the one-year number needed to treat to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published RCT data. The CNT to prevent one event of the single endpoint of CVM was analyzed as a secondary outcome. We performed a sensitivity analysis to mitigate primary differences between the RCTs. Drug costs were calculated as 75% of the US National Average Drug Acquisition Cost listing in June 2020. Results: The CNT to prevent one MACE with subcutaneous semaglutide in SUSTAIN-6 is $641,823 ($402,021-$3,533,533) compared to $855,040 (95% CI: $420,840-∞) with oral semaglutide in PIONEER 6. The lower cost of subcutaneous semaglutide was confirmed in a sensitivity analysis simulating the effects of the drugs in both RCTs. The CNT to prevent one CVM with semaglutide is $16,342,560 ($2,020,704.00-∞) compared to $1,315,720 (95% CI: $921,004-$8,392,414) with oral semaglutide. Conclusions: Subcutaneous semaglutide prescribed for the prevention of MACE in patients with T2DM is moderately cost-saving compared to oral semaglutide for the same purpose. However, for the prevention of CVM, the oral version provides significantly better economic value.

Introduction: The AHA 2020 strategic goal of reducing CV mortality by 20% was partially achieved (15% reduction 2011-2019). Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 inhibitor and oral semaglutide, the first oral glucagon-like peptide 1 receptor agonist, both significantly reduce the incidence of cardiovascular mortality (CVM) in patients with type 2 diabetes (DM) and established CVD. However, the addition of either drug to current diabetes treatment regimens may impose a significant burden on healthcare systems. Hypothesis: Empagliflozin provides more value for money than oral semaglutide for the prevention of CVM in patients with DM. Methods: We calculated the cost needed to treat (CNT) to prevent one case of CVM using either drug, by multiplying the annualized number needed to treat (NNT) to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published randomized controlled trials (RCT) data. We performed a sensitivity analysis to mitigate the primary differences between the RCTs and other uncertainties. Drug costs were calculated as 75% of the US National Average Drug Acquisition Cost listing in June 2020. Results: The annualized NNT of empagliflozin in EMPA-REG-OUTCOME was 141 (95% CI: 104-230) versus 140 (95% CI: 98-893) for oral semaglutide in PIONEER 6, while the corresponding annual costs are $4,572 versus $6,680. Therefore, the CNT of empagliflozin was $644,652 ($475,488-$1,051,560) compared to $935,200 (95% CI: $654,640-$5,965,240) with oral semaglutide. The lower CNT of empagliflozin was confirmed in a sensitivity analysis. Conclusions: The annualized NNT of empagliflozin and oral semaglutide prescribed for the prevention of CVM in patients with T2DM and established CVD is similar. Therefore, the lower cost of empagliflozin results in a lower CNT and better value for money.

Background Icosapent ethyl (IPE) is approved for the prevention of major adverse cardiovascular events (MACE) in patients with hypertriglyceridemia. However, due to budget constraints, access to IPE will inevitably be limited to a fraction of eligible patients. To help maximize value for money spent, we estimated the number of preventable MACE when providing IPE for primary versus secondary prevention. Methods The number of preventable MACE was estimated by dividing the available budget by the cost needed to treat (CNT) to prevent one MACE. CNT was calculated as the product of the number needed to treat (NNT) to prevent 1 MACE by therapy cost. NNT values were determined according to the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) results. The budget limit was set as the United States’ threshold suggested by the Institute for Clinical and Economic Review. Sensitivity analysis was performed regarding the cost of IPE in the United States. Results The NNT to prevent 1 MACE over 4.9 years in the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial primary prevention cohort was 59 (95% confidence interval [CI]: 24-∞) versus 14 (11-21) for secondary prevention. At an annual IPE cost of $2915, the CNT to prevent 1 MACE was $842,726 (95% CI: $342,804-∞) and $199,969 ($157,118-$299,953) accordingly. A total of $819 million worth of IPE can avoid 4762 MACE (95% CI: 0-11,707) versus 20,069 (13,379-25,541), when provided as primary versus secondary prevention therapy; P Conclusions Prioritizing IPE therapy for patients with an established cardiovascular disease may provide significantly more value for money than primary prevention.