Correspondence

Our follow-up study of infants who had been and Others

enrolled in a randomized trial in which two Drs. Peacock and Greenough contributed equally to this
types of ventilation were prescribed showed that letter.
the use of HFOV in the neonatal period was not thisA letter
complete list of authors is available with the full text of
at NEJM.org.
associated with superior respiratory or func- The views expressed are those of the authors and not neces-
tional outcomes at 16 to 19 years of age. Longer- sarily those of the National Health Service, the National Insti-
term follow-up is required to determine whether tuteSupported
for Health Research, or the Department of Health.
by the National Institute for Health Research
there will be premature onset of chronic pulmo- Biomedical Research Centre at Guy’s and St. Thomas’ Na-
nary disease in this vulnerable population. tional Health Service Foundation Trust and King’s College
London.
Christopher Harris, M.R.C.P.C.H. Disclosure forms provided by the authors are available with
King’s College London the full text of this letter at NEJM.org.
London, United Kingdom
Janet L. Peacock, Ph.D. 1. Zivanovic S, Peacock J, Alcazar-Paris M, et al. Late outcomes
Dartmouth College of a randomized trial of high-frequency oscillation in neonates.
Hanover, NH N Engl J Med 2014;​370:​1121-30.
2. Johnson AH, Peacock JL, Greenough A, et al. High-frequency
Anne Greenough, M.D. oscillatory ventilation for the prevention of chronic lung disease
King’s College London of prematurity. N Engl J Med 2002;​347:​633-42.
London, United Kingdom
anne​.­greenough@​­kcl​.­ac​.­uk DOI: 10.1056/NEJMc2008677

The Covid-19 Pandemic and the Incidence

of Acute Myocardial Infarction
To the Editor: During the Covid-19 pandemic,
reports have suggested a decrease in the number
of patients presenting to hospitals because of
emergency conditions such as acute myocardial
infarction.1,2 We examined this issue using data
from Kaiser Permanente Northern California, a
large integrated health care delivery system with
21 medical centers and 255 clinics that provides
comprehensive care for more than 4.4 million
persons throughout Northern California.3
We examined patient characteristics and week-
ly incidence rates of hospitalization for acute
myocardial infarction (ST-segment elevation myo-
cardial infarction [STEMI] or non–ST-segment
elevation myocardial infarction [NSTEMI]) among
adults in the Kaiser Permanente system before
and after the first reported death from Covid-19
in Northern California on March 4, 2020.4 We
compared these data with data from the same
period in 2019. Incidence rates (events per
100,000 person-weeks) for the Covid-19 period
(March 4 through April 14, 2020) were calcu-
lated and compared with those from the pre–
Covid-19 period (January 1 through March 3,
2020), and incidence rates from January 1
through April 14, 2020, were compared with
those from the corresponding period in 2019
(January 1 through April 15, 2019). In addition,
incidence rates for each week from March 5
through April 15, 2019, were compared with
those in the period from January 1 through
March 4, 2019. Incidence rate ratios were used to
compare the relative change in event rates be-
tween the periods and were calculated for key
patient subgroups. Details are provided in the
Supplemental Methods section in the Supple-
mentary Appendix, available with the full text of
this letter at NEJM.org.
Data from 43,017,810 person-weeks from Jan-
uary 1 through April 14, 2020, were evaluated.
The weekly rates of hospitalization for acute
myocardial infarction decreased by up to 48%
during the Covid-19 period. From January 1
through March 3, 2020, a total of 1051 hospital-
ization events occurred (incidence rate, 4.1 per
100,000 person-weeks), and from April 8 through
April 14, 2020, a total of 61 hospitalization events
occurred (incidence rate, 2.1 per 100,000 person-
weeks) (incidence rate ratio, 0.52; 95% confi-
dence interval [CI], 0.40 to 0.68; P<0.001) (Fig. 1,
and Table S2 in the Supplementary Appendix).
Decreases were similar among patients with

n engl j med 383;7  nejm.org  August 13, 2020

The New England Journal of Medicine

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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

March 4, 2020 March 19, 2020

First reported death Shelter-in-place
from Covid-19 in order in California
8 Northern California implemented

Covid-19
7

Hospitalization for Acute MI or Covid-19 6

(rate per 100,000 person-weeks)

4
2019,
Acute MI
3

2020,
2 Acute MI

0
7

14

28

11

18

25

10

17

24

31

14
–2
1–

1–
b.

ch
8–

5–
–

4–

8–
–
Fe
15

22

12

19

18

25
11
ar
n.

ril
ch

ril
n.

b.
–

M
Ja

Ap
n.

b.
n.

b.

ch

ch
ch
29

Fe

Ap
Ja

ar
–
Fe

Fe
Ja

Ja

ar

ar
ar
26

M
n.

M
M
Ja

b.
Fe

Week during 2020

No. of Patients
2019, Acute MI 140 125 104 97 110 118 106 100 107 106 123 102 98 101 98
2020, Acute MI 118 101 115 127 126 105 129 106 124 102 83 73 69 65 61
2020, Covid-19 0 0 0 0 0 0 0 0 0 6 26 58 156 195 207

Figure 1. Incidence of Hospitalization for Acute MI before and during the Covid-19 Pandemic in 2020
and during the Same Period in 2019, Relative to the Incidence of Hospitalization for Covid-19.
Shown are data from the Kaiser Permanente Northern California health system. The data shown in red are the esti-
mated weekly incidence rates of hospitalization for acute myocardial infarction (MI) per 100,000 person-weeks during
the period from January 1 through April 14, 2020. I bars indicate 95% confidence intervals. The data shown in yellow
are the same estimates for January 1 through April 15, 2019. The numbers of days in the 2019 and 2020 periods are
identical because of the leap year in 2020. The data shown in blue are the numbers of hospitalized patients with a
diagnosis of Covid-19 per 100,000 person-weeks (according to the inpatient census at the start of each weekly period).
The 95% confidence intervals are not adjusted for multiple testing and therefore should not be used to ­infer definitive
effects.

NSTEMI (incidence rate ratio, 0.51; 95% CI, 0.38 2020, the prevalences of preexisting coronary
to 0.68) and those with STEMI (incidence rate artery disease, previous acute myocardial infarc-
ratio, 0.60; 95% CI, 0.33 to 1.08) (Fig. S1 and tion, and percutaneous coronary intervention
Table S2). The decrease seen in the comparison were lower than among those who presented
of the Covid-19 period with the pre–Covid-19 during the pre–Covid-19 period (from January 1
period in 2020 was similar to the decrease seen through March 3, 2020) and among those who
in the comparison of the Covid-19 period in 2020 presented from January 1 through April 15, 2019.
with the same weekly periods in 2019 (Fig. 1, However, demographic characteristics, hemody-
Fig. S1, and Table S3). namic measures (vital signs) on admission, initial
Among patients who presented during the and peak troponin I values, and the burden of
Covid-19 period from March 4 through April 14, other examined coexisting conditions were

n engl j med 383;7  nejm.org  August 13, 2020

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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
 Correspondence
similar in patients who presented during the
Covid-19 period and in those who presented
from January 1 through March 3, 2020, and in
those who presented from January 1 through
April 15, 2019 (Table S4). Decreases in hospital-
izations for acute myocardial infarction accord-
ing to patient age (<65 years or ≥65 years), sex,
and the presence or absence of diabetes are
shown in Table S5.
In a large diverse community setting in Cali-
fornia, the incidence of hospitalization for acute
myocardial infarction declined after March 4,
2020, during the Covid-19 pandemic, more than
would be expected on the basis of typical sea-
sonal variation alone. Similar findings have been
noted in northern Italy.5
Matthew D. Solomon, M.D., Ph.D.
Kaiser Permanente Oakland Medical Center
Oakland, CA
matthew.d.solomon@kp.org
Edward J. McNulty, M.D.
Kaiser Permanente San Francisco Medical Center
San Francisco, CA
Jamal S. Rana, M.D., Ph.D.
Kaiser Permanente Oakland Medical Center
Oakland, CA
Thomas K. Leong, M.P.H.
Catherine Lee, Ph.D.
Atezolizumab and Bevacizumab in Hepatocellular Carcinoma
To the Editor: There is a strong rationale for
combining immunotherapy with vascular endo-
thelial growth factor (VEGF) inhibitors in the
treatment of advanced hepatocellular carcinoma,1
and the IMbrave150 trial reported by Finn et al.
(May 14 issue)2 shows an impressive 42% lower
hazard of death with atezolizumab–bevacizumab
than with sorafenib. Unfortunately, the median
overall survival could not be evaluated at the time
of the primary analysis. We extracted data on
overall survival from 14 phase 3, randomized,
controlled trials of first-line therapies for ad-
vanced hepatocellular carcinoma3 and computed
the median follow-up time with the most wide-
ly used reverse Kaplan–Meier method4 in the
“prodlim” package of R software. The median of
the median follow-up time of these trials was
24.5 months (interquartile range, 16.4 to 30.2).
n engl j med 383;7  nejm.org  August 13, 2020
The New England Journal of Medicine
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
Sue-Hee Sung, M.P.H.
Kaiser Permanente Northern California
Oakland, CA
Andrew P. Ambrosy, M.D.
Kaiser Permanente San Francisco Medical Center
San Francisco, CA
Stephen Sidney, M.D., M.P.H.
Alan S. Go, M.D.
Kaiser Permanente Northern California
Oakland, CA
Supported by grants from the Permanente Medical Group De-
livery Sciences and Applied Research and Physician Researcher
programs.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
This letter was published on May 19, 2020, at NEJM.org.
1. Krumholz HM. Where have all the heart attacks gone? New
York Times. April 6, 2020.
2. Garcia S, Albaghdadi MS, Meraj PM, et al. Reduction in ST-
segment elevation cardiac catheterization laboratory activations
in the United States during COVID-19 pandemic. J Am Coll Car-
diol 2020 April 9 (Epub ahead of print).
3. Gordon NP. Characteristics of adult health plan members in
Kaiser Permanente’s Northern California region, as estimated
from the 2011 member health survey. Oakland, CA:​Division of
Research, Kaiser Permanente Medical Care Program, April 2013.
4. Graff A. California reports its first coronavirus death. San
Francisco Chronicle. March 4, 2020.
5. De Filippo O, D’Ascenzo F, Angelini F, et al. Reduced rate of
hospital admissions for ACS during Covid-19 outbreak in north-
ern Italy. N Engl J Med 2020;​383:88-9.
DOI: 10.1056/NEJMc2015630
Surprisingly, the IMbrave150 trial had the short-
est median follow-up time (9.9 months) among
the randomized, controlled trials (see the table in
the Supplementary Appendix, available with the
full text of this letter at NEJM.org). The fact that
the median follow-up time of the IMbrave150
trial is similar to the median overall survival ob-
served with the other first-line therapies, which
is also approximately 10 months, arouses the
concern of data immaturity. This is in stark con-
trast to the CheckMate 459 trial (nivolumab vs.
sorafenib), which, although it did not show a sig-
nificant benefit of nivolumab with respect to
overall survival, had a sufficiently long median
follow-up time of 30.6 months.5 Longer follow-up
is required to ascertain the benefit of atezolizu­
mab–bevacizumab for advanced hepatocellular
carcinoma.