International Journal of Cardiology 308 (2020) 15–19

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Hemodynamic gain index in women: A validation study

Baruch Vainshelboim a,⁎,1, Peter Kokkinos b,1, Jonathan Myers a,1
a
Cardiology Division, Veterans Affairs Palo Alto Health Care System/Stanford University, Palo Alto, CA, USA
b
Washington DC Veterans Affairs Medical Center, Washington, DC, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: A previous study showed a strong and independent association between hemodynamic gain index
Received 21 August 2019 (HGI) and all-cause mortality in a large cohort of men. The current study aimed to validate the association be-
Received in revised form 14 March 2020 tween HGI and all-cause mortality in a pilot cohort of women.
Accepted 27 March 2020 Methods: The cohort included 606 women aged 54.1 ± 12 years who were prospectively followed for 8.0 ±
Available online 30 March 2020
5.7 years. HGI was calculated according to a previously developed equation using heart rate (HR) and systolic
blood pressure (SBP) responses from treadmill exercise testing [(HRpeak*SBPpeak)-(HRrest*SBPrest)]/
Keywords:
Exercise testing
(HRrest*SBPrest). Bivariable and multivariable Cox hazard models were analyzed for HGI and all-cause mortality.
Heart rate Results: During the follow-up, 48 participants (7.9%) died, and mean HGI was 1.86 ± 0.82 bpm/mmHg. In contin-
Blood pressure uous bivariable and multivariable models, each one unit higher in HGI was associated with 64% and 45% reduced
Mortality risks of mortality, respectively. The corresponding hazard ratios and 95% confidence intervals were: 0.36,
(0.22–0.57), and 0.55 (0.33–0.91) (both p b 0.001). In a bivariable categorical model, compared to participants
below the 25th percentile (HGI b1.27), participants who were between the 25th and 50th (HGI 1.27 to 1.77),
50th to 75th (HGI 1.78 to 2.39) and N75th percentile (HGI ≥2.4) exhibited 57%, 90% and 79% reductions in mor-
tality risk (p trend b0.001), respectively.
Conclusions: This validation study in women confirms that a higher HGI is associated with lower risk of all-cause
mortality, supporting its prognostic value for risk stratification in clinical and research settings.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction use a standard exercise test without metabolic or invasive assessments

Exercise testing is a well-established clinical procedure, providing
valuable diagnostic and prognostic information for patients with a
wide spectrum of chronic conditions. Hemodynamic responses during
exercise testing are central for the evaluation of cardiovascular function,
diagnosis of cardiovascular disease, and overall prognosis [1–3]. Despite
many advances in in the applications of the exercise test, knowledge re-
garding the prognostic utility of hemodynamic responses [heart rate
(HR) and blood pressure] has changed very little [1–4]. Chronotropic in-
competence, hypotension, and impaired HR recovery are well-known
abnormal hemodynamic responses associated with cardiovascular dis-
ease and poor prognosis [1–4]. Although these established hemody-
namic responses are endorsed by exercise testing guidelines, they
reflect different physiologic attributes during an exercise test, and pro-
vide only partial and compartmental information on the hemodynamic
response [1,2,5]. Given that many clinical and research centers primarily
⁎ Corresponding author at: VA Palo Alto Health Care System, Cardiology 111C, 3801
Miranda Ave, Palo Alto, CA 94304, USA.
E-mail address: baruch.v1981@gmail.com (B. Vainshelboim).
1
This author takes responsibility for all aspects of the reliability and freedom from bias
of the data presented and their discussed interpretation.
[6], an inexpensive, simple, practical and sensitive comprehensive he-
modynamic marker could potentially be useful to optimize hemody-
namic assessment and enhance risk stratification from an exercise
test. In our previous work, we have introduced a newly developed he-
modynamic gain index (HGI) as a powerful prognostic marker of all-
cause mortality in large cohort of men [7]. The current study aimed to
validate the association between HGI and all-cause mortality in a sepa-
rate cohort of women.
2. Methods
2.1. Participants and study design
The cohort was drawn from the Veterans Exercise Testing Study
(VETS) at the VA Palo Alto Health Care System (n = 9877) and the Ex-
ercise Testing and Health Outcomes Study (ETHOS) from the VA
Washington DC Medical Center (n = 2591). In brief, these cohorts are
ongoing, prospective evaluations of Veteran participants referred for ex-
ercise testing for clinical reasons including evaluation of cardiometa-
bolic risk, signs or symptoms suggestive of cardiovascular disease, or
known cardiometabolic disease. The study is designed to address exer-
cise test, clinical, and lifestyle factors and their association with health

https://doi.org/10.1016/j.ijcard.2020.03.066
0167-5273/© 2020 Elsevier B.V. All rights reserved.
16 B. Vainshelboim et al. / International Journal of Cardiology 308 (2020) 15–19
outcomes. The study was approved by the respective Institutional Re-
view Boards at each institution, and all participants gave their written
informed consent prior to undergoing the exercise test. All participants
who underwent exercise tests in these centers between 1987 and 2012
were considered for inclusion in the study. Of 12,468 participants who
completed a baseline evaluation, 11,844 participants were excluded
from the analysis; men (n = 11,826) and those with conditions that
prevented them from completing the exercise test (orthopedic or neu-
rological reasons or those that required emergent intervention) (n =
18). A total of 606 female participants were included in the current anal-
ysis who were followed for a mean of 8.0 ± 5.7 years. Clinical informa-
tion on diagnoses, risk factors and health behaviors were collected at
the time of the exercise test using the Veterans Affairs Computerized Pa-
tient Record System (CPRS) and self-report health history.
2.2. Exercise testing
Participants underwent symptom-limited treadmill exercise testing
according established guidelines [5,8]. An individualized treadmill ramp
protocol was utilized at the VA Palo Alto Health Care System and a Bruce
protocol was used at the VA Washington DC Medical Center. A 12-lead
electrocardiogram, heart rate, manual blood pressure and the Borg
6–20 perceived exertion scale were continuously recorded throughout
the tests and standard criteria for test termination were used [5,8]. Par-
ticipants were instructed to continue their regular medication regimen
on the day of testing and exercise to volitional fatigue in the absence of
clinical indications for stopping. Cardiorespiratory fitness (CRF)
expressed in metabolic equivalents (METs) was calculated from peak
treadmill speed and grade for the individualized ramp protocol, and ex-
ercise time for the Bruce protocols, utilizing the well-established meta-
bolic equations from the American College of Sports Medicine [5].
2.3. Hemodynamic gain index
The HGI was calculated using heart rate (HR) and systolic blood
pressure (SBP) responses from the exercise tests using the previously
developed equation: HGI = [(HRpeak*SBPpeak)-(HRrest*SBPrest)]/
(HRrest*SBPrest) [7]. The current study extends the analysis of HGI to a
separate cohort of women. Additional validations including correlation
between HGI and CRF [6], and adjusting the continuous models for po-
tential confounders were also conducted.
2.4. Outcomes ascertainment
The Veterans Affairs CPRS was used for capturing all-cause mortality
as the primary outcome. Previous reports have demonstrated that the
Veterans Affairs death records are relatively complete compared to
those from other sources, such as the Social Security Administration
[9] and they have good agreement (kappa = 0.82 to 0.91) with state
death records [10]. Death records were carefully reviewed by qualified
medical personal who were otherwise blinded to treadmill test results
and other study information. International Classification of Diseases
ninth and tenth edition codes were utilized to capture death cases.
The vital status for each participant was ascertained as of August 2016.
2.5. Statistical analysis
SPSS (IBM, Chicago, IL, USA) version 23 was used for statistical anal-
yses. The significance level was set at p b 0.05. Demographic, clinical and
physiological data of the participants are presented as mean ± standard
deviation for continuous variables and in percentages for categorical
variables. Descriptive statistics using the quartiles b25th, 25 to 50th,
50 to 75th, N75th percentiles were used for categorical analysis of HGI.
Participants' data were compared between the quartiles using analysis
of variance for continuous variables and chi-square tests for categorical
variables. The risk association between HGI and all-cause mortality was
assessed using Cox proportional hazard analysis in continuous and cat-
egorical models. For the continuous model, both bivariable and multi-
variable analyses were used. The multivariable model was adjusted for
age, body mass index, smoking, hypertension (SBP ≥ 140 and or
DBP ≥ 90 mmHg or anti-hypertensive therapy), dyslipidemia (total cho-
lesterol ≥200 or LDL cholesterol ≥130 or HDL cholesterol b40 mg/dL or
on lipid-lowering medications) [5], diabetes, presence of cardiovascular
disease, and medications affecting hemodynamics (beta-blockers, cal-
cium channel blockers, angiotensin-converting enzyme inhibitor/angio-
tensin receptor blockers and diuretic drugs). Bivariable Cox hazard
analysis for HGI quartiles was utilized for the categorical model.
Kaplan-Meier survival curves and log-rank tests were used for compar-
isons between the HGI quartiles. The proportional hazards assumption
was evaluated graphically for HGI quartiles and confirmed using the
scaled Schoenfeld residuals. In order to address potential for reverse
causality bias, a secondary analysis was performed after excluding par-
ticipants who had less than two years follow up. Pearson's correlations
were conducted between HGI and CRF and exploratory analysis was
performed for the risk association between peak rate pressure product
(HR*SBP) and death using a Cox proportional hazard model. Data report
and presentations were followed the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) guidelines [11].
3. Results
The analytic sample included 606 women, aged 54.1 ± 12 years. De-
mographic, clinical and physiological characteristics of the participants
are presented in Table 1. Participants at lower compared to higher HGI
quartiles were older, had higher prevalence of cardiovascular disease,
and presented compromised hemodynamics with lower CRF (Table 1).
During 8.0 ± 5.7 years follow-up, 48 participants died. Both in continu-
ous and categorical models, higher HGI was associated with lower risk
of all-cause mortality (Figs. 1, 2 and Table 2). After exclusion of those
with less than two years follow up, HGI remained a significant predictor
of mortality both in multivariable continuous and in bivariable categor-
ical models. The hazard ratio and 95% CI for the continuous model was
0.40, (0.24 to 0.66), p b 0.001 for each one unit increase in HGI. Com-
pared to those who were below the 25th percentile, the hazard ratios
and 95% CI in the categorical model were 0.54 (0.27 to 1.1) for the
25th and 50th percentiles, 0.12 (0.03 to 0.51) for the 50th to 75th per-
centiles, and 0.21 (0.05 to 0.9) for N75th percentile, p trend =0.005.
The correlation between HGI and CRF was r = 0.52, R2 = 0.27,
p b 0.001. Both in bivariable and multivariable hazard models, peak
rate pressure product (HR*SBP) alone was not associated with
mortality.
4. Discussion
In the current validation study, we aimed to assess the prognostic
value of previously introduced hemodynamic gain index (HGI) in a sep-
arate cohort of women. Consistent with our previous report in men [7],
the findings demonstrated that higher HGI is inversely and indepen-
dently associated with lower risk of all-cause mortality in women. HGI
remained a significant predictor of mortality after adjusting for
established chronic conditions, age, medications affecting hemodynam-
ics and exclusion of those with less than two years follow up. HGI only
moderately correlated with CRF, strengthening its additional utility be-
yond CRF. Along with previous findings in men, these results support
the prognostic value of HGI in women, providing validation and poten-
tial application for clinical and research settings.
The results of the current study align with established literature of
hemodynamic responses to exercise and mortality risk [1–3]. The find-
ings are also consistent with our previous work in men [7], providing
validation for the prognostic utility of HGI in women. Although previous
hemodynamic markers have been shown to be associated with adverse
cardiovascular outcomes, each has limitations in terms of evaluating
 B. Vainshelboim et al. / International Journal of Cardiology 308 (2020) 15–19 17

Table 1
Demographic and clinical characteristics of women cohort.

Clinical history and demographics Entire cohort HGI HGI HGI HGI p value
(n = 606) b25th percentile 25 to 50th percentiles 50 to 75th, percentiles N75th percentile
(n = 151) (n = 148) (n = 155) (n = 152)

Age (years) 54.1 ± 12 59.5 ± 12.2 53.9 ± 12.3 51.4 ± 10.5 50.2 ± 9.5 b0.001
Body mass index (kg/m2) 29.4 ± 7.1 29 ± 6.8 30 ± 8.7 30.1 ± 9.2 30.3 ± 6 0.507

Clinical history
Family history of coronary artery disease 24.4% 24.5% 28.4% 20.6% 23% 0.547
Hypertension 45.9% 48.3% 50% 43.2% 41.4% 0.389
Dyslipidemia 32% 25.8% 31.8% 34.8% 34.9% 0.284
Obesity (body mass index ≥30) 41.6% 41% 38.2% 44.9% 44.3% 0.663
Any cardiovascular disease 4.9% 11.3% 4.7% 3.2% 0.7% b0.001
Any pulmonary disease 9.8% 11.5% 11.9% 6.9% 5.6% 0.518
Diabetes 8.2% 8.6% 7.7% 11.6% 0% 0.463
Smoking 11.7% 9.3% 10.1% 14.2% 13.2% 0.483

Hemodynamics
Resting Heart Rate (bpm) 76.2 ± 13.6 84.1 ± 16 80.2 ± 11.5 74.2 ± 10 66.4 ± 9 b0.001
Peak heart rate (bpm) 148.6 ± 22.2 129.8 ± 23 147.6 ± 19.4 147.3 ± 18.8 156 ± 17.4 b0.001
Percent of predicted maximal heart rate (%)(220-age) 87.6 ± 11.9 78.4 ± 13.5 87.1 ± 10.8 91.3 ± 7.4 94.1 ± 7.4 b0.001
Resting systolic blood presure (mmHg) 123 ± 18 132.4 ± 21.9 125.3 ± 16.3 120 ± 15.4 114 ± 12.9 b0.001
Resting diastolic blood presure (mmHg) 75.9 ± 10.4 79.8 ± 11.4 77.7 ± 10 74.7 ± 9.3 72.2 ± 9.7 b0.001
Peak systolic blood presure (mmHg) 172.5 ± 27.3 158.6 ± 26.4 172 ± 26 175.6 ± 25.7 183 ± 25.2 b0.001
Peak diastolic blood presure (mmHg) 81.7 ± 14 81.2 ± 15.1 82.9 ± 12.4 81.1 ± 13.4 81.6 ± 14.8 0.681
Hemodynamic gain index (bpm/mmHg) 1.86 ± 0.82 0.87 ± 0.3 1.53 ± 0.14 2.1 ± 0.18 2.9 ± 0.5 b0.001
Cardiorespiratory fitness (METs) 8.2 ± 2.8 6 ± 2.3 7.9 ± 2.4 9.1 ± 2.7 9.8 ± 2.3 b0.001

Medications
Any drugs affecting hemodynamics 43.6% 46.4% 41.9% 43.2% 42.1% 0.854
Anti-hyperlipidemias drugs 21% 16.6% 20.3% 25.2% 21.7% 0.319
Deaths (n/%) 48/7.9% 32/21.2% 11/7.4% 2/1.3% 3/2% b0.001
Follow up time (years) 8 ± 5.7 10.4 ± 6.4 8.9 ± 5.6 7.5 ± 5.3 5.3 ± 3.9 b0.001

Data presented as means ± standard deviations or % for categorical variables. HGI; hemodynamic gain index. Hypertension was defined as systolic blood pressure ≥140 and or diastolic
blood pressure ≥90 mmHg or anti-hypertensive therapy, dyslipidemia was defined as total cholesterol ≥200 and or LDL cholesterol ≥130 and or HDL cholesterol b40 mg/dL or on lipid-
lowering medication [5].

hemodynamic function [1,2,5]. For instance, achieving a maximal
HR b 85% of age-predicted, the first minute of HR recovery b12 bpm
and a hypotensive SBP response to exercise reflect different hemody-
namic abnormalities and are measured at separate time points during
the exercise test. Independently, these variables express only a fraction
of the hemodynamic response to an exercise test and lack the integra-
tion of both heart rate and blood pressure responses into one compre-
hensive metric [1,2,5]. HGI offers a more integrated evaluation of heart
rate and blood pressure responses to exercise in a single index, provid-
ing a simple yet powerful non-invasive evaluation of the hemodynamic
response to exercise [4].
Potential physiological mechanisms of HGI may relate to its
surrogate reflection of cardiovascular function [4,8,12]. HGI is
composed of the net gain in rate pressure product divided by rest-
ing values, expressing the net responsiveness of the major hemo-
dynamics in reference to the resting function. The rate pressure
product is an indirect marker of myocardial oxygen uptake and is
associated with cardiac function and prognosis in patients with
coronary artery disease [4,5,8]. HGI incorporates the concept of
net gain (from rest to peak exercise) in rate pressure product,
which may reflect indirectly the cardiovascular function. HGI was
also positively correlated with CRF (r = 0.52), a well-established
marker of all-cause and cardiovascular mortality [6]. Overall, the
higher the HGI the better the cardiovascular function. On the
other hand, a low HGI may suggest a non-invasive reflection of
myocardial and vascular stiffness [4,8,12,13].

Fig. 1. Hazard ratios of hemodynamic gain index percentiles and all-cause mortality in women. HGI; hemodynamic gain index.
18 B. Vainshelboim et al. / International Journal of Cardiology 308 (2020) 15–19

Fig. 2. Survival curves of hemodynamic gain index percentiles in women. HGI; hemodynamic gain index.

4.1. Study limitations previous findings in men [7], providing reasonable confidence for gen-
eralization. Second, Veteran participants are a unique population with
The strengths of the current study include the application of non- a rich mixture of co-morbidities that may have influenced the results
invasive and easily assessable physiological variables (HR and SBP), uti- by selection bias. Nevertheless, HGI aligns with a well-established
lization of separate cohort of women for validation of HGI and extended body of knowledge of physiological responses and exercise testing
prospective follow-up (8 years) for adverse outcomes. Mortality out- guidelines as well as with our previous cohort of men [1,2,5,7]. Third, al-
comes were verified through the Veterans Affairs computerized medical though participants' characteristics were consistent with a general US
records system, which has been demonstrated to be comparatively ac- population [17], information regarding insulin depended and non-
curate and complete [9,10]. The study has also several limitations. depended diabetes, as well as emerging cardiovascular disease risk fac-
First, although sample size and the number of deaths were sufficient tors such as pathological pregnancies, gestational diabetes or hyperten-
for conducting continuous fully adjusted risk analysis, the number of sion, preeclampsia, polycystic ovarian syndrome, menopausal age,
deaths in each HGI quartile were insufficient for multivariable analysis hormone replacement therapy, rheumatic diseases, depression and can-
in the categorical model (Table 1) [14–16]. This will require a future cer treatment were not available in the current study [18]. Forth, partic-
larger study in women. However, the results in both continuous and ipants underwent a standardized treadmill exercise testing [5,8],
categorical models were strongly significant and consistent with the spectral analysis of the electrocardiogram was not available. Finally, al-
though the findings provide a strong association between HGI and mor-
tality, they do not demonstrate causality.
Table 2
Bivariable and multivariable Cox hazard analyses for all-cause mortality in women.
5. Conclusion
Variables Hazard ratios p
95% (confidence value
interval)
This validation cohort of women supports our previous report of
HGI, suggesting that HGI is a potentially powerful prognostic marker
Bivariable analysis
for mortality. The current results suggest that higher HGI is indepen-
Age (for each one year increase) 1.06 (1.04–1.09) b0.001
Smoking 1.61 (0.68–3.81) 0.279 dently associated with lower risk of all-cause mortality in women. HGI
Hypertension 0.98 (0.55–1.73) 0.937 could potentially complement other prognostic markers from the exer-
Hypercholesterolemia 0.18 (0.04–0.77) 0.02 cise test and provide additional information for risk stratification. Future
Body mass index (for each one unit increase) 0.94 (0.89–0.99) 0.011
studies are needed to assess changes in HGI over time and risk of health-
Cardiovascular disease 3.1 (1.51–6.2) 0.002
Diabetes 1.72 (0.97–3) 0.06 related outcomes.
Medications affecting hemodynamics 1.8 (0.99–3.1) 0.051
Hemodynamic gain index (for each 1 unit 0.36 (0.22–0.57) b0.001 CRediT authorship contribution statement
increase)

Multivariable analysis Baruch Vainshelboim:Conceptualization, Methodology, Validation,

Age (for each one year increase) 1.05 (1.02–1.08) 0.001 Formal analysis, Investigation, Writing - original draft, Writing - review
Smoking 2.72 (1.01–7.3) 0.047 & editing.Peter Kokkinos:Validation, Investigation, Resources, Data
Hypertension 0.6 (0.3–1.2) 0.156
curation, Writing - review & editing.Jonathan Myers:Validation, Inves-
Hypercholesterolemia 0.25 (0.06–1.1) 0.06
Body mass index (for each one unit increase) 0.96 (0.91–1.01) 0.116 tigation, Resources, Data curation, Writing - review & editing.
Cardiovascular disease 1.4 (0.66–3.1) 0.370
Diabetes 1.8 (0.99–3.2) 0.056 Declaration of competing interest
Medications affecting hemodynamics 1.6 (0.8–3.3) 0.192
Hemodynamic gain index (for each 1 unit 0.55 (0.33–0.91) 0.019
increase)
None.

The multivariable risk model included age, smoking, hypertension, hypercholesterolemia,

Acknowledgment
body mass index, cardiovascular disease, diabetes, medications affecting hemodynamics
and hemodynamic gain index.
Values in bold are statistically significant. None.
 B. Vainshelboim et al. / International Journal of Cardiology 308 (2020) 15–19
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