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Vaccine safety is critical for the successful implementation of any vaccination program, especially during a pandemic. In February 1976, the Centers for Disease Control and Prevention confirmed a cluster of cases of severe influenza-like illness among Army recruits at Fort Dix, New Jersey.1 A swine influenza A strain that resembled the 1918 pandemic influenza strain was identified,2 and a vaccination program was subsequently initiated for the entire U.S. population. After more than 40 million persons were vaccinated, a small excess risk of Guillain–Barré syndrome was noted, with an attributable risk of approximately 1 case per 100,000 doses administered. Given these concerns and because the pandemic did not materialize, the vaccination program was halted in December 1976 so that the issue could be explored further. This experience shed light on the need for real-time vaccine safety surveillance and the importance of context in decision making during a pandemic.

In a study now reported in the Journal by Barda et al., the investigators simultaneously evaluated the risk of adverse events among persons (≥16 years of age) who had received the BNT162b2 vaccine (Pfizer–BioNTech) and the risk of the same events after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.3 The authors used data from the largest integrated payer–provider health care organization in Israel, in conjunction with data on SARS-CoV-2 polymerase-chain-reaction tests and data on coronavirus disease 2019 (Covid-19) vaccine administration from the Israeli Ministry of Health.

This use of multiple data sets highlights the importance of investment in digital capabilities and meaningful integration across systems in order to provide real-time answers to key public health questions. The design of rigorous postauthorization vaccine safety studies during the Covid-19 pandemic has been a challenge because the pandemic itself has caused changes in health care utilization, the rollout of Covid-19 vaccines has occurred in phases because of initial supply limitations, and there have been disparities in access to vaccines. Barda et al. broadly addressed many of these challenges by emulating a trial that matched eligible vaccinees to unvaccinated controls according to sociodemographic characteristics, the number of preexisting chronic health conditions, previous health care utilization, and pregnancy status.

In the vaccination analysis, the study included 42 days of follow-up (i.e., 21 days after the first dose and 21 days after the second dose). This analysis accounted for seasonal and secular trends by matching on the day of vaccination, rather than relying on historical risk estimates that may not have been comparable in the pandemic setting. In the SARS-CoV-2 analysis, a similar approach was used to match persons with a newly diagnosed infection to uninfected persons.

Although the risk estimates in the vaccination and the SARS-CoV-2 analyses were not directly comparable because of differences in the populations (i.e., events were evaluated per 100,000 vaccinated persons and per 100,000 infected persons, respectively), these risks were placed in context. The most salient example is myocarditis, which has received much attention recently given the preponderance of reported cases after vaccination among adolescents and young adults and the incidence of myocarditis observed after SARS-CoV-2 infection.4-6 In the population-based cohort in the study conducted by Barda and colleagues, the risk ratios for myocarditis were 3.24 (95% confidence interval [CI], 1.55 to 12.44) after vaccination and 18.28 (95% CI, 3.95 to 25.12) after SARS-CoV-2 infection, with risk differences of 2.7 events per 100,000 persons (95% CI, 1.0 to 4.6) and 11.0 events per 100,000 persons (95% CI, 5.6 to 15.8), respectively. What is even more compelling about these data is the substantial protective effect of vaccines with respect to adverse events such as acute kidney injury, intracranial hemorrhage, and anemia, probably because infection was prevented. Furthermore, the persons with SARS-CoV-2 infection appeared to be at substantially higher risk for arrhythmia, myocardial infarction, deep-vein thrombosis, pulmonary embolism, pericarditis, intracerebral hemorrhage, and thrombocytopenia than those who received the BNT162b2 vaccine.

National discussions about benefit–risk balance often focus on the benefits of preventing symptomatic disease, hospitalization, or death due to Covid-19 and the risks of serious adverse events after vaccination.7,8 As specific adverse events such as myocarditis are highlighted, however, the lack of corresponding specificity about benefits can hamper efforts to communicate effectively with patients. Messenger RNA (mRNA) vaccines may be associated with myocarditis, but they can also prevent cases of myocarditis, acute kidney injury, arrhythmia, and thromboembolic disease. The key to comparing these risks depends on the risk of SARS-CoV-2 infection to an individual person, and that risk can vary according to place and over time. Given the current state of the global pandemic, however, the risk of exposure to SARS-CoV-2 appears to be inevitable.

One major limitation of this study is the lack of risk estimates according to age group and sex. For example, thrombosis with thrombocytopenia syndrome occurs predominantly in young adult women who have received adenoviral vector vaccines against SARS-CoV-2, whereas myocarditis predominantly occurs in male teens and young men who have received mRNA vaccines.5,9,10 Age- and sex-stratified comparisons that reflect local epidemiologic factors might support public understanding of different approaches to vaccine use in different countries, such as Israel, the United Kingdom, and the United States. Other limitations of the study include the paucity of data regarding younger teens and children, the conservative assumption that vaccines have no effect on transmission, and the absence of medical record review to validate computable phenotypes (i.e., algorithms used to identify a cohort on the basis of patient records).

As new knowledge of the safety and benefits of vaccines continues to evolve, studies like this one may help to support decision making about the use of Covid-19 vaccines. The benefit–risk balance should be reassessed, refined, and communicated as the disease burden changes, new variants and safety signals emerge, and vaccine effectiveness begins to wane. Context matters, which means that we as a country need to be ready for continual learning and change.

Vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome, is a rare but potentially fatal complication of vector-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines.1-3 The clinical picture and the serologic findings in patients with VITT resemble heparin-induced thrombocytopenia.1-3 Several groups have reported the presence of platelet factor 4 (PF4)–reactive antibodies in patients with VITT.1-3 IgG from patients with VITT induces platelet activation and aggregation by cross-linking Fcγ receptor IIA on platelets.1 PF4 is a tetrameric protein that is released from platelet alpha granules on activation. VITT antibodies bind to the heparin-binding site on PF4.4 The link between vaccination and the formation of anti-PF4 antibodies is yet to be determined. A proposed mechanism includes cross-reactivity between anti–SARS-CoV-2 and anti-PF4 antibodies.5 In the current study, we investigated the correlation between anti–PF4–heparin antibodies and anti–SARS-CoV-2 antibodies in vaccinated health care workers (healthy controls) and in vaccinated patients with clinically suspected VITT.

The level of anti–PF4–heparin antibodies was measured with the use of an enzyme-linked immunosorbent assay (ELISA), and the levels of antibodies against various antigenic sites of the SARS-CoV-2 spike protein (spike trimer, receptor-binding domain [RBD], subunit 1 [S1] domain, and subunit 2 [S2] domain) and against nucleocapsid protein were measured with the use of a bead-based assay (Luminex). Antibodies were measured in 101 healthy controls 2 weeks after the first dose of ChAdOx1 nCoV-19 (Oxford–AstraZeneca) had been administered and in 59 patients with clinically suspected VITT between 11 and 22 days after the first dose had been administered. The ability of the sera to activate platelets was tested with the use of a modified heparin-induced platelet aggregation assay. Details of the methods are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.

Figure 1.

Antibody Levels and Correlation Analysis.
VITT was confirmed in 20 of 59 patients (34%) on the basis of a positive PF4 ELISA and a positive modified heparin-induced platelet aggregation assay (Table S1 in the Supplementary Appendix). The level of anti–PF4–heparin antibodies was higher among the patients with confirmed VITT than among the healthy controls and the patients who did not have VITT (Figure 1A and Table S1). The 95% confidence intervals for the differences between the groups are presented in Table S2; these confidence intervals were not adjusted for multiplicity and therefore cannot be used to infer effects. The levels of antibodies against spike trimer, RBD, S1 domain, and nucleocapsid protein were similar in the three groups. The levels of antibodies against S2 domain were lower among the patients who did not have VITT than among the persons in the other two groups. We did not find any correlation between the level of anti–PF4–heparin antibodies and the level of anti–SARS-CoV-2 IgG antibodies in any of the three groups (Figure 1B and Table S3).

Moreover, the levels of anti–SARS-CoV-2 antibodies did not differ substantially between vaccinated persons without complications (i.e., the healthy controls) and patients with VITT. Similarly, Scully et al.2 reported that the levels of antibodies to spike protein and RBD in patients with VITT were in the same range as those of the recipients of one dose of ChAdOx1 nCoV-19. Furthermore, our study did not show a correlation between anti–PF4–heparin antibodies and anti–SARS-CoV-2 antibodies in patients with VITT. Although a preprint publication suggested that spike protein shares an immunogenic epitope with PF4, purified anti-PF4 and anti–PF4–heparin antibodies from patients with VITT did not show cross-reactivity to recombinant SARS-CoV-2 spike protein.5

Our results do not support the hypothesis that the immune response against SARS-CoV-2 proteins leads to the formation of anti-PF4 antibodies in patients with VITT. However, we cannot exclude the possibility of cross-reactivity between a subgroup of anti–SARS-CoV-2 antibodies and a subgroup of anti-PF4 antibodies. A better understanding of the link between vaccination and VITT is necessary for the development of more targeted therapies.

Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear.

METHODS
In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days.

RESULTS
A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P=0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups.

The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear.

METHODS
In this multicenter, randomized, controlled trial, we assigned Chinese patients 60 to 80 years of age with hypertension to a systolic blood-pressure target of 110 to less than 130 mm Hg (intensive treatment) or a target of 130 to less than 150 mm Hg (standard treatment). The primary outcome was a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes.

RESULTS
Of the 9624 patients screened for eligibility, 8511 were enrolled in the trial; 4243 were randomly assigned to the intensive-treatment group and 4268 to the standard-treatment group. At 1 year of follow-up, the mean systolic blood pressure was 127.5 mm Hg in the intensive-treatment group and 135.3 mm Hg in the standard-treatment group. During a median follow-up period of 3.34 years, primary-outcome events occurred in 147 patients (3.5%) in the intensive-treatment group, as compared with 196 patients (4.6%) in the standard-treatment group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.92; P=0.007). The results for most of the individual components of the primary outcome also favored intensive treatment: the hazard ratio for stroke was 0.67 (95% CI, 0.47 to 0.97), acute coronary syndrome 0.67 (95% CI, 0.47 to 0.94), acute decompensated heart failure 0.27 (95% CI, 0.08 to 0.98), coronary revascularization 0.69 (95% CI, 0.40 to 1.18), atrial fibrillation 0.96 (95% CI, 0.55 to 1.68), and death from cardiovascular causes 0.72 (95% CI, 0.39 to 1.32). The results for safety and renal outcomes did not differ significantly between the two groups, except for the incidence of hypotension, which was higher in the intensive-treatment group.

We often lament the lack of confirmatory studies that can either reassure us all that the previous evidence for a trialed intervention is robust or indicate that the evidence is questionable. Zhang and colleagues have conducted such a study — the STEP trial1 — which in essence investigates the veracity of the findings of the previous trial SPRINT,2 but in an older cohort and in China, a country with a considerable burden of high blood pressure and stroke. The investigators have demonstrated impressive organizational skills in completing recruitment for such a large multicenter trial within a calendar year. As in . . .

Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain.

METHODS
We conducted an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia.

RESULTS
A total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval [CI], 0.77 to 0.96; P=0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P<0.001) and death (39.28 events vs. 44.61 events per 1000 person-years; rate ratio, 0.88; 95% CI, 0.82 to 0.95; P<0.001). The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37; P=0.76).