cirrhosis and liver cancer mortality in the united states · 2012. 2. 18. · confidential: for...

Confidential: For Review Only

Cirrhosis and Liver Cancer Mortality in the United States

1999-2015: An Observational Study

Journal: BMJ

Manuscript ID BMJ.2018.043691

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 12-Feb-2018

Complete List of Authors: Tapper, Elliot; University of Michigan, Parikh, Neehar; University of Michigan

Keywords: liver disease, hepatitis, falls, alcohol, hepatocellular carcinoma

https://mc.manuscriptcentral.com/bmj

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Cirrhosis and Liver Cancer Mortality in the United States 1999-2015: An

Observational Study

Elliot B. Tapper MD (1,2) and Neehar D Parikh MD MS (1,2)

1. Division of Gastroenterology and Hepatology, University of Michigan

2. Gastroenterology Section, VA Ann Arbor Healthcare System, Ann Arbor

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Keywords: Liver disease, hepatitis, falls, alcohol, liver cancer

Word count: 2,681

Corresponding author: Elliot B. Tapper, MD 3912 Taubman, SPC 5362

1500 E Medical Center Dr Ann Arbor, MI 48109 T: (734) 647-9252 F: (734) 936-7392 e: [email protected] Disclosure: 1. Elliot Tapper is the guarantor of this article 2. Roles

a. Concept: Tapper, Parikh b. Analysis: Tapper, Parikh c. Data acquisition: Tapper, Parikh d. Writing: Tapper, Parikh

3. Conflicts of interest: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work 4. Funding: Elliot Tapper receives funding from the National Institutes of Health through the Michigan Institute for Clinical and Health Research (KL2TR002241). 5. The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution and convert or allow conversion into any format including without limitation audio, iii) create any other derivative work(s) based in whole or part on the on the

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Contribution, iv) to exploit all subsidiary rights to exploit all subsidiary rights that currently exist or as may exist in the future in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above 6. The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted.

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Abstract

Objectives: Cirrhosis and hepatocellular carcinoma (HCC) are morbid and costly conditions,

each marked by the development of fatal, resource intensive complications. National data

regarding trends in demographics and associated causes of liver disease mortality are lacking.

We aimed to describe mortality by age-group, sex, race, state of residence, and comorbidity.

Design: Observational cohort study

Setting: Death certificate data from the Vital Statistics Cooperative and population data from the

US Census Bureau compiled by the Center for Disease Control and Prevention’s Wide-ranging

Online Data for Epidemiologic Research (1999-2015).

Participants: US residents

Main outcome measures: Mortality. Trends evaluated using Joinpoint Regression.

Results: Age-adjusted mortality due to cirrhosis was stable from 1999-2009 (7.5/100,000 to

7.4/100,000) but then increased each year through 2015 to 9.1/100,000 while HCC mortality

plateaued. The age group with the greatest increase in mortality is 25-34, overall average annual

increase of 10.5% (95%CI 8.9-12.2%), largely driven by death due to alcoholic cirrhosis.

Whites, American Indians and Hispanics have experienced the greatest increase in cirrhosis

mortality. Death due to concomitant peritonitis, sepsis, and falls are among the fastest growing

associated comorbid diagnoses. Western and Southern US have the greatest increase in cirrhosis

mortality while the West has the greatest increase in HCC mortality.

Conclusions: Disparate changes in cirrhosis mortality by age, race, liver disease etiology, and

US region necessitate tailoring of preventative plans to inform rational public health outreach.

The trends related to deaths from infections, falls, and the rapid rise in death-rates among young

persons due to alcohol highlight new challenges for optimal care of patients with liver disease.

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What this paper adds?

What is already known on this subject?

- Cirrhosis is a morbid condition that is increasing in prevalence

- Although hepatitis C is being eradicated, the burden of alcoholic liver disease and

Nonalcoholic Fatty Liver Disease is increasing

What this study adds

- Mortality due to cirrhosis is increasing in the US since 2009

- Persons aged 25-34 experienced the greatest increase in mortality with an average annual

increase of 10.5% (95%CI 8.9-12.2%) driven by death due to alcoholic cirrhosis.

- Specific demographic subgroups – namely Whites, American Indians and Hispanics –

have experienced the greatest increase in cirrhosis mortality.

- Cirrhosis mortality is improving in Massachusetts and the District of Columbia but worst

in Kentucky, New Mexico, Wyoming, and Arizona.

- Cirrhosis mortality related to falls, sepsis

- Trends in liver cancer mortality are worst in Idaho, Oregon, and Texas.

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Introduction

� Cirrhosis, the end result for most chronic liver diseases,1 is characterized by fatal,

resource-intensive complications. These include hepatocellular carcinoma (HCC), hepatic

encephalopathy (which also causes falls), gastrointestinal hemorrhage, infections, and renal

failure. Compounding the problem, the prevalence of cirrhosis in the United States (US) has

doubled in the last decade.2 3 Although hepatitis C (HCV), a major cause of cirrhosis, could be

eradicated given recently widely available effective antiviral therapy, this trend is likely to

continue.4 Even in the coming post-HCV era, deaths due to cirrhosis are expected to triple by

2030,5 driven primarily by the increasing prevalence of nonalcoholic fatty liver disease

(NAFLD) in parallel with rising obesity rates.6 7

Cirrhosis and HCC carry personal, social, and financial burdens for patients, their

families, and society. They are disabling,8 stressful for caregivers,9 and resource intensive even

in death where terminal hospitalizations cost in excess of $50,000 per-patient.10 Prevention and

early management of cirrhosis is therefore cost-effective.11-13 However, nationally representative

data to guide the optimal allocation of resources and preventive efforts are limited, particularly

regarding differential mortality by demographic subgroups or regions of the country.14 Herein, to

fill this gap, we analyze the Center for Disease Control and Prevention’s Wide-ranging Online

Data for Epidemiologic Research (CDC WONDER) platform.��

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Methods

All data were obtained CDC WONDER platform.15 For more details on CDC Wonder

please see the Supplemental Material. Our primary aim was to describe temporal trends in

death-rates attributable to cirrhosis (ICD-10 K70.3, K74.5, and K74.6) and HCC (C22.0) as the

primary/underlying cause. All rates obtained were age-adjusted, standardized to the 2000 US

population using the direct method unless otherwise indicated. Secondarily, we sought to

describe how these trends differed based on demographic subgroups; age, sex, race (Asian

Pacific Islander, American Indian/Alaska Native, black/African American, and

white/Caucasian), Hispanic ethnicity, and place of residence. We also aimed to describe trends in

causes of death related to specific complications associated with cirrhosis. Specifically, we

examined death due to gastrointestinal hemorrhage (ICD-10 K25-K28, K92.0-K92.2, I85.0),

peritonitis (K65), sepsis (A41), hepatorenal syndrome (K76.7), or falls (W00-W19) in patients

with cirrhosis. Given the association between NAFLD and complications of the metabolic

syndrome like cerebrovascular disease and ischemic heart disease (I20-I25, I60-I69),16 we also

assessed trends in death-rates due to these conditions.

To test for unmeasured secular trends, all findings were compared to non-cirrhotic

control populations. Some controls were pre-selected to reflect death-rates for chronic disease,

cancer, and infection. Specifically, we examined the trends in deaths due to cardiovascular

disease (ICD-10 I00-I99), cerebrovascular disease and ischemic heart disease (I20-I25, I60-I69),

colon cancer (C18), and sepsis (A41). Other controls were selected post-hoc based on trends

observed in our study. These included deaths due to alcohol use disorder (F10), peritonitis, falls,

and end-stage renal disease (N18.0, N18.5). Finally, we assessed overall trends in several states

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that had the greatest increase or highest death-rates due to cirrhosis and HCC (e.g. Arizona, New

Mexico, and Wyoming).

Data Analysis

Trends in death-rates were then evaluated using the National Cancer Institute’s Joinpoint

program (version 3.5.2; available: http://surveillance.cancer.gov/joinpoint), which uses a

piecewise linear regression approach to determine whether rates over time are best described by

a single line or by multiple linear segments (i.e., none or >1 joinpoints). We allowed a maximum

of 3 joinpoints with a minimum of 3 observations per segment. The best model (in which

additional joinpoints did not improve model fit) was identified using log-transformed data. We

obtained the annual percentage change (APC) in death-rates over each linear segment as well as

the average annual percentage change (AAPC) from 1999-2015 for each model. The APC was

obtained using Monte-Carlo permutation analysis to fit a series of 4,500 randomly permuted

straight lines on a logarithmic scale to observed rates to estimate APC, resulting in trends of

variable length. Trends were only described as increasing or decreasing when the APC was

significantly different from 0 (two-tailed P<0.05). We noted many significant changes in the

APC beginning at 2009. We therefore provided the AAPC for 2009-2015. We created state heat-

maps, highlighting the age-adjusted death-rate in each state for 3 evenly-spaced study years

(1999, 2008, 2015). We also compared trajectories in death-rate by contrasting the AAPC with

each state’s baseline death-rate and the AAPC before and after 2009. Patients were not involved

in the study design. As this is a publically available dataset of de-identified data, no ethics

approval was obtained.

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Results

Overall Trends (Table 1)

During the study period, cirrhosis caused a total of 426,575 deaths (20,669 in 1999 and

33,973 in 2015) and 125,869 were attributed to HCC (5,112 in 1999 and 10,059 in 2015). Since

1999 when the death rate from cirrhosis per 100,000 Americans was 7.53 (95%CI7.42-7.63),

there has been a 1.1% (95%CI0.7-1.6) average annual increase in cirrhosis related mortality.

This rate, however, has risen more rapidly since 2009 (AAPC: 3.4% 95%CI3.2-3.8). Deaths

related to HCC have risen by an AAPC 2.0% (95%CI1.6-2.4) yearly since 1999. In contrast to

cirrhosis trends, the rate of HCC related deaths have slowed since 2009 (AAPC: 1.2%

95%CI0.3-2.1). (Supplementary Table 1) Males had a higher burden of age-adjusted cirrhosis

mortality when compared to females by a 2:1 ratio and a higher burden of HCC related deaths by

a nearly 4:1 ratio. The highest burden of age-adjusted cirrhosis mortality was seen in American

Indians (16.5/100,000 people), followed by whites (8.1/100,000 people). Age-adjusted HCC

death-rates were highest in Asian/Pacific Islander patients. Hispanics had relatively high age-

adjusted mortality from both cirrhosis (12.4/100,000) and HCC (3.7/100,000). The Southern and

Western regions of the US had the highest age-adjusted mortality from cirrhosis (8.7/100,000

and 8.5/100,000, respectively) while the Western US alone had the highest age adjusted

mortality related to HCC (2.7/100,000).

Cause-Specific Mortality Trends

Supplementary Table 1 depicts the time trends in comorbid causes of death for patients

who died from cirrhosis. The AAPC for cirrhosis-related deaths due to peritonitis (1.9%

95%CI0.8-3.0), sepsis (3.7% 95%CI3.2-4.1), cerebrovascular and ischemic heart disease (0.4%

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95%CI0.1-0.7), and falls (4.5% 95%CI3.5-4.5) have risen since 1999. Conversely, deaths due to

cirrhosis and gastrointestinal bleeding or hepatorenal syndrome have fallen or remained stable

from 1999-2015, with respective AAPC of -0.8%(95%CI-1.3- -0.4) and -0.3%(95%CI-0.9- 0.3).

Similar changes were observed when specific codes for variceal hemorrhage (ICD-10 I85.9) and

comorbid end-stage renal disease (N18.0, N18.5) were examined. However, despite

improvements in death-rates for these conditions, all gains were made from 1999-2008. When

examining the trends from 2009-2015, the death-rate associated with each potential cirrhosis-

related complication we queried, including fatal bleeding and renal failure, have risen. Notably,

from 2009-2015 the magnitude of increased death-rate due to peritonitis and sepsis rose

substantially with respective AAPC of 6.1%(95%CI 4.2-81) and 7.3%(95%CI 6.4-8.1).

Demographic Trends in Death-Rates

Cirrhosis

We evaluated trends in cirrhosis death-rates in demographic subgroups with several

significant findings.(Table 2) First, cirrhosis-related mortality increased significantly from 2009-

2015. Although several subgroups had significant declines in cirrhosis-related mortality from

1999-2008, these trends reversed in nearly every demographic subgroup beginning in 2009.

Second, both sexes experienced similar increases in mortality. Third, whites and American

Indians had more rapid increase in cirrhosis mortality after 2009 with AAPC of 3.9%(95%CI

3.4-4.5) and 3.8%(95%CI 1.5-6.3) compared to African Americans. Fourth, non-Hispanic

patients experienced a slower rise in cirrhosis related mortality than Hispanic patients. Fifth, in

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recent years, the Northeast US had the slowest rise (AAPC 1.5% 95%CI 0.9-2.2) while the south

had the fastest (3.9% 95%CI3.2-4.6).

Though the incidence of cirrhosis-related mortality was lower in young people, persons

aged 25-34 experienced the highest AAPC in cirrhosis mortality; 3.7% (95%CI2.4-5.1) over the

whole period and 10.5% (95%CI8.9-12.2) from 2009-2015.(Figure 1) Whites and American

Indians had the most rapid increase in this age group. Increased death-rates in the 25-34 age

group were driven by alcoholic cirrhosis, where the average AAPC from 2009-2015 was 15.3%

(95%CI 13.0-17.7) compared to 6.3% 95%CI3.6-9.0 for other causes of cirrhosis. These finding

is reinforced by Supplementary Figure 1 which demonstrates parallel changes in mortality due

to both alcohol use disorder and alcoholic liver disease.�

Hepatocellular Carcinoma

The demographic trends in mortality from HCC are markedly different from cirrhosis.

First, overall, from 1999-2011 there was a 2.4% (95%CI:2.1-2.8) increase in HCC mortality

nationally. Since 2011, the death-rate has plateaued. Females experienced a consistent increase

in HCC mortality through 1999-2015 while HCC death-rates for males plateaued beginning in

2011. Second, American Indians experienced continuous increases in HCC mortality while

Whites experienced increased HCC mortality only in recent years (since 2011). By contrast,

Asian/Pacific Islanders had consistent decrease in HCC mortality since 1999 while African

Americans had a plateau in HCC mortality since 2011. Third, all US regions except for the

Northeast experienced increased HCC mortality since 1999. Fourth, as seen in Figure 1, while

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HCC related mortality has decreased in younger patients (<55 years) since 2009, mortality

among those >55 years-old increased during the same timeframe.

State-Level Variation in Mortality

The fastest rise in cirrhosis and HCC related mortality occurred in the Western and

Southern US. In Figure 2, we show that the highest mortality and greatest increases in mortality

were observed in Southern, Western and Mid-Western states from 1999-2015. Figure 3A

contrasts changes in mortality for cirrhosis and HCC with the baseline mortality rate for

individual states. The states with the greatest AAPC in cirrhosis related mortality include

Wyoming 3.7% (95%CI1.9-5.6), Oregon 2.9% (95%CI1.6-4.2), Arkansas 2.8% (95%CI1.4-4.3),

and Iowa 2.8% (95% CI1.6-3.9). Five states experienced decreases in cirrhosis related deaths,

with the largest decrease observed in the District of Columbia -2.1 (95%CI-4.1- -0.1).

We also evaluated state-level trends in HCC-related death-rates. No state experienced a

decreasing mortality due to HCC (Figure 3B). Many of the same states with worsening cirrhosis

mortality also experienced worsening HCC mortality (e.g. Oregon, Iowa). However, some states

experienced increased HCC-related deaths out-of-sync with cirrhosis trends. These include

Arizona (5.1% 95%CI3.7-6.5), Kansas (4.3% 95%CI2.8-5.8), Kentucky (4.0% 95%CI3.1-5.0),

and Washington (3.9% 95%CI3.1-4.6).

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In Figure 3C-D, we compare the AAPC for mortality in the first half of the study period

(1999-2008) to the AAPC in the last half of the study period (2009-2015). In the lower left

quadrant of Fig.3C are the only 2 states (Washington DC and Massachusetts) that experienced

consistent improvements in cirrhosis-mortality. In contrast, the upper right quadrant has all states

with consistently worsening death-rates (e.g. Oregon, Idaho, Alabama). In the left upper

quadrant are those states with reversals from improvements to worsening (e.g. New York,

Connecticut, Kentucky, Utah). The contribution to these trends from alcohol use disorder is

explored by demonstrating death-rates by state in Supplementary Figure 2. In some cases, they

are consistent with cirrhosis trends (e.g. Oregon), and not in others (e.g. Massachusetts). With

respect to HCC,(Fig.3D) no state observed an improvement from 2009-2015 while Western and

Southern states experience the worst trends.

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Secular Trends (1999-2015)

In Supplementary Table 2, we compare the cirrhosis-specific trends to other conditions

to assess for the presence of unmeasured secular trends. First, death trends for broader definitions

of liver disease (including all liver-related ICD-10 codes) were not different than a definition that

focused on cirrhosis codes. Second, death-rates due to heart disease and colon cancer fell while it

rose for cirrhosis. Third, whereas death due to gastrointestinal hemorrhage and peritonitis

increased for patients with cirrhosis since 2009, they did not rise in patients without coding for

cirrhosis. Sepsis death-rates increased minimally in the non-cirrhotic population from 2009-2015

(AAPC 1.2%(95%CI0.1-2.3), but increased by 7.3%(95%CI6.4-8.1) per year in cirrhosis

patients. Fourth, while death-rates fell for non-cirrhotic patients in Arizona, New Mexico, and

Wyoming, death-rates due to cirrhosis in each state rose substantially.

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Discussion

Cirrhosis and HCC are deadly conditions, each with increasing footprints in American

public health. Understanding the factors associated with mortality due to these conditions will

inform how best to allocate resources. In this study of national data from 1999-2015, we find 6

major trends in cirrhosis and HCC mortality in the US.

First, we show mortality due to cirrhosis has been rising since 2008. Whereas Asrani et al

previously demonstrated unchanged age-and-sex-adjusted death-rates due to liver disease from

1979 (25.8/100,000) to 2008 (25.7/100,000) in Olmstead county,17 our analysis shows increased

mortality in the context of declining mortality due to other causes such as heart disease and colon

cancer. Second, increased cirrhosis mortality disproportionately affects young persons aged 25-

34, White, American Indian, and Hispanic Americans, and those living in the Southern or

Western US. Third, increases in cirrhosis mortality among young people appears to be driven by

alcohol use disorder. Fourth, while mortality due to HCC continues to increase in older

Americans, it is decreasing in younger people and Asians. This could be due to increasing the

early detection of HCC, application of curative/locoregional therapies, and, because hepatitis B

is the principal cause of HCC worldwide and among Asian-Americans, effective vaccines and

antiviral therapy for hepatitis B.18-21 These trends also parallel those observed for the incidence

of HCC.22 Fifth, the causes of death associated with cirrhosis that had the most consistent and

substantial increases over the study period were infections and falls. Common complications of

cirrhosis such as hepatic encephalopathy and sarcopenia (both prevalent in up to 40% of patients

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with cirrhosis23), while not directly fatal themselves, both increase the risk of mortality due to

falls, frailty, and infection.8 24-26 Finally, specific states in the South and West experienced the

worst trends for cirrhosis and HCC mortality. Only Massachusetts and the District of Columbia

claimed consistent reductions in cirrhosis mortality. Adverse trends in Kentucky, New Mexico,

Wyoming, and Arizona in particular require further study for explanation. The areas of greatest

need for attention to HCC mortality appear to be Idaho, Oregon, and Texas.

Clinical and Health-Policy Implications

Cirrhosis is morbid and costly to treat and therefore efforts to prevent progression of all

liver diseases are cost-effective.12 13 27 28 Our data highlight several modifiable sources of

mortality. First, young American Indians and Whites with benefit from intensified resources for

alcohol use disorders. Second, falls in patients with cirrhosis are associated with hepatic

encephalopathy, frailty, and psychoactive medications such as benzodiazepines.24 29 30 Falls could

be prevented through early identification and treatment of mild hepatic encephalopathy, ensuring

adequate nutrition, enrollment in physical activity programs, and targeted campaigns for

psychoactive medication deprescribing. Third, patients with a history of spontaneous bacterial

peritonitis experience improved survival from secondary (antibiotic) prophylaxis, yet many do

not receive it.31 Quality improvement efforts are needed optimize care delivery in these cases.31

Fourth, research and outreach are required to understand and contextualize the factors associated

with the adverse trends identified in many states.

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Contextual Factors

Several considerations must be made in the interpretation of these findings. First, these

findings are based on data abstracted from death certificates. Death certificates may be

inaccurate (in up to 15% of cases32) and this study does not explicitly validate disease coding

with chart review. For this reason, we chose the diagnostic codes most specific to cirrhotic

complication. Still, sensitivity analyses using a variety of coding algorithms for liver disease

confirm consistency of results and comparisons of our results to other conditions imply

independence from secular trends. Second, given variance in coding for hepatitis C (substantial

changes after 2004), we cannot provide mortality estimates specific to viral hepatitis. Third,

though we have detected worsening mortality since 2009, the precise explanations for this trend

require further study. For example, we identify the most at-risk states, but granular data is needed

to determine root-causes, be they trends in healthcare access, policy (e.g. alcohol tax-rates),

alcohol abuse, or the differential changes in the comorbidities of a given state’s population.

Fourth, it is unclear how these trends are – or will be – affected direct-active antivirals for

HCV. Screening for HCV is recommended given the availability of highly efficacious therapy,

however hundreds of thousands of individuals in the US have undetected HCV or do not have

access to antiviral therapy.13 33 At the same time, HCV eradication will prevent the development

of cirrhosis and its complications, potentially changing these trends if re-assessed in the next 5-

10 years. However, HCV therapy cannot modify the significant trends observed related to

alcohol or the expected increase in the burden of NAFLD.5

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Conclusion

Specific demographic subgroups and states are disproportionately affected by adverse

trends in cirrhosis and HCC-related mortality. Additionally, patients with cirrhosis are more

likely to die due to specific secondary causes including falls and infections. These data

underscore gaps in care and opportunities for prevention.

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Deaths Crude rate

(per 100,000) Age-adjusted (per 100,000) Deaths

Crude rate (per 100,000)

Age-adjusted (per 100,000)

Overall 426,575 8.34 (8.32-9.37) 7.80 (7.78-7.83) 125,869 2.46 (2.45-2.48) 2.27 (2.26-2.29)

Female Male

150,232 276,343

5.78 (5.75-5.81) 11.0(10.9-11.0)

5.13 (5.11-5.16) 10.8 (10.8-10.8)

29,187 96,682

1.12 (1.11-1.14) 3.85 (3.82-3.87)

0.97 (0.95-0.98) 3.82 (3.79-3.84)

American Indian Asian/PI

African American White

8,354 6,117

37,825 374,279

12.9 (12.7-13.2) 2.31 (2.26-2.37)

5.5 (5.4-5.6) 9.14 (9.11-9.17)

16.5 (16.1-16.9) 2.87 (2.80-2.95)

6.3 (6.2-6.4) 8.14 (8.11-8.17)

1,254 10,460 19,468 94,687

1.94 (1.83-2.05) 3.96 (3.88-4.03) 2.83 (2.79-2.87) 2.31 (2.30-2.33)

3.00 (2.82-3.18) 4.89 (4.79-4.98) 3.32 (3.27-3.37)

2.01 (2.00 – 2.02)

Hispanic Non-Hispanic

58,622 366,472

7.52 (7.46-7.59) 8.46 (8.43-8.48)

12.4(12.3 – 12.5) 7.38(7.35-7.40)

15,695 109,819

2.01 (1.98-2.05) 2.53 (2.52-2.55)

3.69 (3.63-3.75) 2.16 (2.15-2.17)

Northeast Midwest

South West

66,721 84,264

173,547 102,043

7.15 (7.10-7.21) 7.49 (7.44-7.54) 9.26 (9.21-9.30) 8.64 (8.59-8.70)

6.34 (6.29-6.39) 6.91 (6.86-6.96) 8.66 (8.62-8.70) 8.54 (8.49-8.59)

23,996 24,172 45,105 32,596

2.57 (2.54-2.61) 2.15 (2.12 – 2.18)

2.41 (2.38-2.43) 2.76 (2.73 – 2.79)

2.24 (2.21 – 2.27) 1.94 (1.92- 1.97)

2.22 (2.20 – 2.24) 2.73 (2.70 – 2.76)

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Joinpoint segment APC (95%CI) P-value

Joinpoint segment APC (95%CI) P-value

Overall

1999-2003 2003-2006 2006-2009 2009-2015

0.2 (-0.6-0.9) -1.5 (-3.6-0.7) 0.6 (-1.5-2.8) 3.4 (3.1-3.8)

0.6 0.1 0.5

<0.001 Overall 1999-2011 2011-2015

2.4 (2.1-2.8) 0.5 (-0.9-2.0)

<0.001 0.4

Female Female Female

Male Male

1999-2002 2002-2008 2008-2015 1999-2009 2009-2015

1.4 (-1.0-3.8) -0.8 (-1.8-0.1)

4.0 (3.5-4.5) -0.6(-0.8- -0.3)

3.2 (2.7-3.7)

0.2 0.1

<0.001 <0.001 <0.001

Female Male Male

1999-2015 1999-2011 2012-2015

1.2 (0.9-1.4) 2.6 (2.3-2.9)

0.3 (-1.0-1.6)

0.02 <0.001

0.6

American Indian American Indian

Asian/Pacific Islander African American African American

White White

1999-2010 2010-2015 1999-2015 1999-2008 2008-2015 1999-2009 2009-2015

-0.3(-1.2-0.6) 3.8(1.5-6.3)

0.2 (-0.3-0.7) -3.7 (-4.3- -3.1)

1.9 (1.9-2.8) 0.1 (-0.2-0.4) 3.9 (3.4-4.5)

0.5 0.004

0.3 <0.001 <0.001

0.4 <0.001

American Indian Asian/Pacific Islander

African American African American

White White

1999-2015 1999-2015 1999-2011 2011-2015 1999-2011 2011-2015

2.3 (0.9-3.7) -2.8 (-3.5- -2.1)

3.1 (2.4-3.8) -1.4 (-4.2 -1.4)

2.6(2.5-2.8) 1.0 (0.2-1.8)

0.003 <0.001 <0.001

0.3 <0.001

0.01

Hispanic Hispanic

Non-Hispanic Non-Hispanic

1999-2009 2009-2015 1999-2007 2007-2015

-0.3 (-0.6 - -0.1) 3.7 (3.2-4.2)

-1.7 (-2.4 - -1.0) 1.3 (0.7-1.8)

0.01 <0.001 <0.001 <0.001

Hispanic Non-Hispanic Non-Hispanic Non-Hispanic

1999-2015 1999-2007 2007-2010 2010-2015

0.5 (-0.01-1.0) 2.0 (1.5-2.4) 4.0 (0.3-7.8)

0.5 (-0.2 – 1.3)

0.1 <0.001

0.04 0.15

Northeast Northeast Midwest Midwest

South South West West

1999-2007 2007-2015 1999-2008 2008-2015 1999-2009 2009-2015 1999-2008 2008-2015

-2.2 (-2.9- -1.5) 1.5 (0.9-2.2)

-0.4 (-0.7- -0.1) 3.1 (2.7-3.5)

-0.2(-0.6-0.1) 3.9 (3.2-4.6)

-0.2(-0.7-0.3) 3.3 (2.6-3.9)

<0.001 <0.001

0.01 <0.001

0.2 <0.001

0.4 <0.001

Northeast Northeast

Midwest South West

1999-2010 2010-2015 1999-2015 1999-2015 1999-2015

2.3(1.7-2.9) -0.2 (-1.9-1.6)

2.4(2.2-2.6) 2.2(1.7-2.6) 1.9(1.5-2.2)

<0.001 0.8

0.001 <0.001 <0.001

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Figure 1: Death-rate Trends by Age-Group

Each bar represents the average annual percentage change in the death-rate due to cirrhosis and

hepatocellular carcinoma (HCC). Panels A and C show changes over 1999-2008; B and D show

changes 2009-2015. Panels A and B: Key trends include increasing cirrhosis mortality for

Americans aged 25-34 and contrasting HCC mortality trends for groups younger (decreasing)

and older (increasing) than 55-65. The magnitude of these trends rises in recent years. Panels C

and D: Trends for both cirrhosis and HCC mortality worsen for patients of white race over all,

American Indian race in the young (age 25-34 from 2009-2015) and appear to improve early in

the study period for young African Americans while they worsen for older African Americans

(age 65-74) in the latter half of the study period.

Figure 2: Age Adjusted Death-rates Attributable to Cirrhosis and Hepatocellular

Carcinoma over Time

The age-adjusted mortality for each condition in each state is presented in quartiles for the first,

middle and last year of the study. Quartiles for each time period are denoted by yellow (first),

light orange (second), dark orange (third), and red (fourth). Striped or shaded states imply data

that is either unreliable or suppressed to protect patient identity.

Figure 3: States with Significant changes in Death-rates Attributable to Cirrhosis and

Hepatocellular Carcinoma

A-B: The average annual percentage change (AAPC) in mortality for each individual state is

plotted against the baseline age-adjusted death-rate for cirrhosis (A) and hepatocellular

carcinoma (HCC, B)

C-D: In order to characterize the trajectory of mortality due to cirrhosis (C) and HCC (D), the

AAPC since 2009 is plotted against the AAPC in the first half of the study (1999-2008) for

individual states.

Note: States without significant trends were excluded from this figure for simplicity.

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Figure 1: Death-rate Trends by Age-Group Each bar represents the average annual percentage change in the death-rate due to cirrhosis and

hepatocellular carcinoma (HCC). Panels A and C show changes over 1999-2008; B and D show changes 2009-2015. Panels A and B: Key trends include increasing cirrhosis mortality for Americans aged 25-34 and contrasting HCC mortality trends for groups younger (decreasing) and older (increasing) than 55-65. The

magnitude of these trends rises in recent years. Panels C and D: Trends for both cirrhosis and HCC mortality worsen for patients of white race over all, American Indian race in the young (age 25-34 from 2009-2015) and appear to improve early in the study period for young African Americans while they worsen for older

African Americans (age 65-74) in the latter half of the study period.

200x148mm (300 x 300 DPI)

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Figure 2: Age Adjusted Death-rates Attributable to Cirrhosis and Hepatocellular Carcinoma over Time The age-adjusted mortality for each condition in each state is presented in quartiles for the first, middle and last year of the study. Quartiles for each time period are denoted by yellow (first), light orange (second),

dark orange (third), and red (fourth). Striped or shaded states imply data that is either unreliable or suppressed to protect patient identity.

190x126mm (300 x 300 DPI)

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Figure 3: States with Significant changes in Death-rates Attributable to Cirrhosis and Hepatocellular

Carcinoma

A-B: The average annual percentage change (AAPC) in mortality for each individual state is plotted against the baseline age-adjusted death-rate for cirrhosis (A) and hepatocellular carcinoma (HCC, B)

C-D: In order to characterize the trajectory of mortality due to cirrhosis (C) and HCC (D), the AAPC since 2009 is plotted against the AAPC in the first half of the study (1999-2008) for individual states.

Note: States without significant trends were excluded from this figure for simplicity.

206x180mm (300 x 300 DPI)

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cirrhosis and liver cancer mortality in the united states · 2012. 2. 18. · confidential: for...

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