Khan, Safi U.

116 Background: The impact of socioeconomic status on genitourinary (GU) cancer mortality in the United States (US) is unclear. Hence, we evaluated the association of the socioeconomic status with GU cancer mortality across the US counties. Methods: County-level age-adjusted mortality rates (AAMR) per 100,000 person-years (PY) for populations diagnosed with GU cancers were abstracted from the wide-ranging online data for epidemiological research (WONDER) database. The agency for toxic substances and disease registry (ATSDR) was queried to obtain county-level social vulnerability indices from 2014-2018. Percentile ranking scores (PRS: ranging from 0-1) were computed for each US county and further categorized into quartiles (Q: 1st: 0-0.25 [least vulnerable]; 4th: 0.75-1.00 [most vulnerable]). AAMRs were then linked with quartile rankings. A population-weighted, Poisson regression analysis was conducted to compute rate ratios (RR) of AAMRs between 4th and 1st Q with the corresponding 95% confidence intervals (CI). Results: A total 3142 US counties were included in this analysis. The AAMR for GU cancers was 22.6 overall deaths (OD) and 4.20 premature deaths (PD; defined as death at age <65 years) per 100,000 PY. GU cancer-related mortality increased in a stepwise fashion from the 1st Q to the 4th Q (OD: 21.6 vs 24.1; PD: 3.48 vs 5.19). In terms of OD by specific GU cancers, significantly higher AAMRs were observed in the 4th Q compared to the 1st Q for patients with prostate cancer (RR; 1.19 [95% CI;1.14-1.24]), and renal cell carcinoma (RCC; 1.12 [1.04-1.21]) but not for those with lower urothelial tract cancers (0.92 [0.87-0.96]). Among subgroups, non-Hispanic Blacks (1.19 [1.07-1.33]), and Hispanics (1.28 [1.08-1.51]) with prostate cancer and men with RCC (1.11; 1.03-1.19) in the 4th Q experienced significantly higher overall mortality when compared to those in the 1st Q. With regards to PD, significantly higher AAMRs were observed in the 4th Q vs 1st Q for patients with prostate cancer (1.54 [1.34-1.77]), and RCC (1.28 [1.12-1.45]). Consistently, men with RCC in the 4th Q also experienced higher premature mortality when compared to the 1st Q. Sparsity of mortality data among different ethnic/racial subgroups across the US counties precluded any formal assessment of disparity by specific GU cancers. A sensitivity analysis, conducted using the weighted linear regression approach, showed consistent results. Conclusions: Population level data suggest that socially vulnerable populations, especially Non-Hispanic Black and Hispanic men with prostate cancer, and men with renal cell carcinoma may be at an increased risk of cancer-related mortality. Hence, there is a dire need to address this mortality gap across different socioeconomic subgroups to ensure health-care equity. Investigations at the patient level are required to further ascertain these findings.

499 Background: The impact of socioeconomic status on gastrointestinal (GI) cancer mortality in the United States (US) is not well-established. We hypothesized that socially vulnerable populations have disproportionately higher mortality rates. Hence, we assessed the association of the social vulnerability index (SVI) with GI cancer mortality across US counties. Methods: Social vulnerability indices were obtained from the agency for toxic substances and disease registry (ATSDR) from 2014-2018 to compute percentile ranking scores (PRS: ranging from 0-1) for each US county. PRS were further categorized into quartiles (Q: 1st: 0-0.25 [least vulnerable]; 4th:0.75-1.00 [most vulnerable]). The wide-ranging online data for epidemiological research (WONDER) database was queried to abstract county-level age-adjusted mortality rates (AAMR) per 100,000 person-years (PY) for populations diagnosed with GI cancers. AAMRs were then linked with quartile rankings. Rate ratios (RR) of AAMRs between 4th and 1st Q were subsequently estimated with 95% confidence intervals using population-weighted, Poisson regression. Results: A total of 3142 counties were included in this analysis. The AAMR for overall deaths (OD) and premature deaths (PD; defined as death at age <65) in the GI cancer population was 53.8 and 17.7 per 100,000 PY. A gradient increase in GI cancer-related mortality was observed from 1st Q to 4th Q (OD: 49.2 vs 59.3; PD: 14.1 vs 21.3). This stepwise increase in AAMR over the quartiles was consistent across gender, different racial/ethnic subgroups, and rural/urban categories of counties. The AAMRs for OD were significantly higher in the 4th Q as compared to the 1st Q for gastric (RR: 1.67 [95% CI, 1.51-1.86]), hepatocellular including intrahepatic biliary (1.52 [1.45-1.61]), colorectal (1.21 [1.16-1.26]) and biliary (1.17 [1.06-1.28]) cancer. Similarly, significantly higher AAMRs for PD were observed in 4th Q vs1st Q for gastric (1.81 [1.60-2.05]), hepatocellular including intrahepatic biliary (1.78 [1.58-2.00]), biliary (1.64 [1.35-1.99]), colorectal (1.29 [1.21-1.39]) and pancreatic (1.16 [1.07-1.25]) cancer. However, no significant differences were observed for esophageal and small intestinal cancers. Men with gastric (1.58 [1.41-1.78]) and hepatocellular cancer (1.54 [1.43-1.66]), non-Hispanic Black population (1.54 [1.31-1.80]) with hepatocellular cancer, and Hispanic population with colorectal cancer (1.50 [1.31-1.72]) were observed to have higher overall mortality in the 4th Q compared to the 1st Q. The findings were similar for premature mortality. Conclusions: Population-level data suggests that the US counties with higher socio-economic adversities may be at an increased risk of GI cancer-related mortality. Investigations using patient-level data are required to probe the impact of socioeconomic vulnerabilities on cancer-related mortality.

Objective: Limited data exist around the receipt of palliative care (PC) in patients hospitalized with common chronic conditions. We studied the independent predictors, temporal trends in rates of PC utilization in patients hospitalized with acute exacerbation of common chronic diseases. Methods: Population-based cohort study of all hospitalizations with an acute exacerbation of heart disease (HD), cerebrovascular accident (CVA), cancer (CA), and chronic lower respiratory disease (CLRD). Patients aged ≥18 years or older between January 1, 2004, and December 31, 2017, referred for inpatient PC were extracted from the National Inpatient Sample. Poisson regression analyses were used to estimate temporal trends. Results: Between 2004 and 2017, of 91,877,531 hospitalizations, 55.2%, 13.9%, 17.2%, and 13.8% hospitalizations were related to HD, CVA, CA, and CLRD, respectively. There was a temporal increase in the uptake of PC across all disease groups. Age-adjusted estimated rates of PC per 100,000 hospitalizations/year were highest for CA (2308 (95% CI 2249–2366) to 10,794 (95% CI 10,652–10,936)), whereas the CLRD cohort had the lowest rates of PC referrals (255 (95% CI 231–278) to 1882 (95% CI 1821–1943)) between 2004 and 2017, respectively. In the subgroup analysis of patients who died during hospitalization, the CVA group had the highest uptake of PC per 100,000 hospitalizations/year (4979 (95% CI 4918–5040)) followed by CA (4241 (95% CI 4189–4292)), HD (3250 (95% CI 3211–3289)) and CLRD (3248 (95% CI 3162–3405)). Conclusion: PC service utilization is increasing but remains disparate, particularly in patients that die during hospital admission from common chronic conditions. These findings highlight the need to develop a multidisciplinary, patient-centered approach to improve access to PC services in these patients.

Background Despite improvements in the management and prevention of stroke, increasing hospitalizations for stroke and stagnant mortality rates have been described in young adults. However, there is a paucity of contemporary national mortality estimates in young adults. Methods and Results Trends in mortality related to stroke in young adults (aged 25–64 years) were assessed using the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research database. Age‐adjusted mortality rates per 100 000 people with associated annual percentage change were calculated. Joinpoint regression was used to assess the trends in the overall sample and different demographic (sex, race and ethnicity, and age) and geographical (state, urban‐rural, and regional) subgroups. Between 1999 and 2019, a total of 566 916 stroke‐related deaths occurred among young adults. After the initial decline in mortality in the overall population, age‐adjusted mortality rate increased from 2013 to 2019 with an associated annual percentage change of 1.5 (95% CI, 1.1–2.0). Mortality rates were higher in men versus women and in non‐Hispanic Black people versus individuals of other races and ethnicities. Non‐Hispanic American Indian or Alaskan Native people had a marked increase in stroke‐related mortality (annual percentage change 2010–2019: 3.3). Furthermore, rural (nonmetropolitan) counties experienced the greatest increase in mortality (annual percentage change 2012–2019: 3.1) compared with urban (metropolitan) counties. Conclusions Following the initial decline in stroke‐related mortality, young adults have experienced increasing mortality rates from 2013 to 2019, with considerable differences across demographic groups and regions.

Objective To determine the harms of ezetimibe in people who need lipid-lowering treatment. Design Systematic review and meta-analysis. Data sources Randomised controlled trials and cohort studies. Eligibility criteria for selecting studies Studies comparing ezetimibe with placebo, standard care, or other lipid-lowering agents in people who need lipid-lowering treatment with a follow-up duration of at least six months (or 24 weeks). The relative effects for potential harms of ezetimibe were pooled by use of random effect pairwise meta-analyses for randomised controlled trials and the evidence from observational studies was narratively summarised. The certainty of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation. Results 48 randomised controlled trials with 28 444 participants (median follow-up 34 weeks, range 24-312 weeks) and four observational studies with 1667 participants (median follow-up 282 weeks, range 72-400 weeks) were included. The meta-analyses of randomised trials showed moderate to high certainty that ezetimibe was not associated with cancer (relative risk 1.01; 95% confidence interval 0.92 to 1.11), fractures (0.90; 0.74 to 1.10), discontinuation due to any adverse event (0.87; 0.74 to 1.03), gastrointestinal adverse events leading to discontinuation (1.34; 0.58 to 3.08), myalgia or muscular pain leading to discontinuation (0.82; 0.51 to 1.33), neurocognitive events (1.48; 0.58 to 3.81), or new-onset diabetes (0.88; 0.61 to 1.28). The narrative analysis of observational studies provided consistent findings. No credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials. Conclusions Ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents. Review registration PROSPERO CRD42020187437.

Abstract Clinical question In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug? Current practice Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients’ values and preferences, absolute benefits and harms and potential treatment burdens. Recommendations The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins. How this guideline was created An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults’ average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform ( www.magicapp.org ) that also allows re-use and adaptation. The evidence A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/ . Understanding the recommendations The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient’s risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients’ cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms. Because of the anticipated large variability of patients’ values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit. The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.

Abstract Objective To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant. Design Network meta-analysis. Data sources Medline, EMBASE, and Cochrane Library up to 31 December 2020. Eligibility criteria for selecting studies Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months. Main outcome measures We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke. Results We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke. Conclusions Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.

Objective To determine the harms of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in people who need lipid-lowering therapy. Methods This systematic review included randomised controlled trials that compared PCSK9 inhibitors with placebo, standard care or active lipid-lowering comparators in people who need lipid-lowering therapy with the follow-up duration of at least 24 weeks. We summarised the relative effects for potential harms from PCSK9 inhibitors using random-effect pairwise meta-analyses and assessed the certainty of evidence using GRADE (Grading of Recommendation Assessment, Development and Evaluation) for each outcome. Results We included 32 trials with 65 861 participants (with the median follow-up duration of 40 weeks, ranging from 24 to 146 weeks). The meta-analysis showed an incidence of injection-site reaction leading to discontinuation (absolute incidence of 15 events (95% CI 11 to 20) per 1000 persons in a 5-year time frame, high certainty evidence). PCSK9 inhibitors do not increase the risk of new-onset diabetes mellitus, neurocognitive events, cataracts or gastrointestinal haemorrhage with high certainty evidence. PCSK9 inhibitors probably do not increase the risks of myalgia or muscular pain leading to discontinuation or any adverse events leading to discontinuation with moderate evidence certainty. Given very limited evidence, PCSK9 inhibitors might not increase influenza-like symptoms leading to discontinuation (risk ratio 1.5; 95% CI 0.06 to 36.58). We did not identify credible subgroup analyses results, including shorter versus longer follow-up duration of trials. Conclusions PCSK9 inhibitors slightly increase the risk of severe injection-site reaction but not cataracts, gastrointestinal haemorrhage, neurocognitive events, new-onset diabetes or severe myalgia or muscular pain.

BACKGROUND The United States (US)‐Mexico border is a socioeconomically underserved area. We sought to investigate whether stroke‐related mortality varies between the US border and nonborder counties. METHODS AND RESULTS We used death certificates from the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research database to examine stroke‐related mortality in border versus nonborder counties in California, Texas, New Mexico, and Arizona. We measured average annual percent changes (AAPCs) in age‐adjusted mortality rates (AAMRs) per 100 000 between 1999 and 2018. Overall, AAMRs were higher for nonborder counties, older adults, men, and non‐Hispanic Black adults than their counterparts. Between 1999 and 2018, AAMRs reduced from 55.8 per 100 000 to 34.4 per 100 000 in the border counties (AAPC, −2.70) and 64.5 per 100 000 to 37.6 per 100 000 in nonborder counties (AAPC, −2.92). The annual percent change in AAMR initially decreased, followed by stagnation in both border and nonborder counties since 2012. The AAPC in AAMR decreased in all 4 states; however, AAMR increased in California’s border counties since 2012 (annual percent change, 3.9). The annual percent change in AAMR decreased for older adults between 1999 and 2012 for the border (−5.10) and nonborder counties (−5.01), followed by a rise in border counties and stalling in nonborder counties. Although the AAPC in AAMR decreased for both sexes, the AAPC in AAMR differed significantly for non‐Hispanic White adults in border (−2.69) and nonborder counties (−2.86). The mortality decreased consistently for all other ethnicities/races in both border and nonborder counties. CONCLUSIONS Stroke‐related mortality varied between the border and nonborder counties. Given the substantial public health implications, targeted interventions aimed at vulnerable populations are required to improve stroke‐related outcomes in the US‐Mexico border area.

AbstractBackgroundRepresentation trends of women, older adults, and ethnic/racial minorities in randomized controlled trials (RCTs) of atrial fibrillation (AF) are uncertain.MethodsWe systematically reviewed 134 AF related RCTs (phase II and III) encompassing 149,162 participants using Medline and ClinicalTrials.gov through April 2019 to determine representation trends of women, older patients (≥75 years), and ethnic/racial minorities. Weighted data on the prevalence of AF from epidemiological studies were used to compare the representation of the studied groups of interest in AF RCTs to their expected burden of the disease.ResultsOnly 18.7% of the RCTs reported proportion of older patients, and 12.7% RCTs reported ethnic/racial minorities. The proportions of women in RCTs versus general population were 35.2% and 35.1%, of Hispanics were 11.9% and 5.2%, of Blacks were 1.2% and 5.7%, of American Indian/Alaskans were 0.2% and 0.2%, of Asians were 14.2% and 2.4%, of native Hawaiian/Pacific Islanders were 0.05% and 0.1% and of non‐Whites were 19.5% and 22.5%, respectively. The weighted mean age (SD) across the trials was 65.3 (3.2) years which was less than the corresponding weighted mean age of 71.1 (4.5) years in the comparative epidemiological data.ConclusionThe reporting of older patients and ethnic/racial minorities was poor in RCTs of AF. The representation of women and American Indian/Alaskan natives matched their expected population share of disease burden. Hispanics and Asians were over‐represented and Blacks, native Hawaiian/Pacific Islanders and non‐Whites were under‐represented in RCTs of AF.