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Background: Cardiovascular disease (CVD) is the leading cause of death and colorectal cancer (CRC) is the third leading cause of death in the United States., Purpose: To systematically review evidence for the effectiveness of aspirin to prevent myocardial infarction (MI), stroke, cardiovascular death, and all-cause mortality in those without a history of CVD. In addition, to review evidence for CRC incidence and mortality associated with aspirin use in primary and secondary CVD populations. To further review harms associated with aspirin use., Data Sources: We searched MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials to identify literature that was published between January 2014 and January 14, 2021. We supplemented our searches with reference lists from the previous review, relevant existing systematic reviews, suggestions from experts, and Clinicaltrials.gov to identify ongoing trials. We conducted ongoing surveillance for relevant literature through January 21, 2022., Study Selection: Two investigators independently reviewed identified abstracts and full text articles against a set of a priori inclusion and quality criteria., Data Analysis: One investigator abstracted data into an evidence table and a second investigator checked these data. We conducted Peto fixed effects meta-analyses to estimate the effect size of aspirin in preventing MI, stroke, CVD-related death and all-cause mortality, CRC incidence and mortality, major bleeding, major gastrointestinal (GI) bleeding, intracranial bleeding, hemorrhagic stroke, and extracranial bleeding. Additionally, we conducted sensitivity analyses using Mantel-Haenszel fixed effects and Restricted Maximum Likelihood random effects., Results: We included 13 fair- to good-quality randomized, controlled trials (RCTs) (N=161,680) examining the effectiveness of aspirin for the primary prevention of CVD. Based on pooled analysis of 11 primary CVD prevention trials using aspirin ≤100 mg/day, low-dose aspirin reduces the risk of major CVD events (total MI, total stroke, CVD mortality) by 10 percent (k=11, N=134,470; Peto odds ratio [OR], 0.90 [95% confidence interval (CI), 0.85 to 0.95]), MI by 11 percent (k=11, N=134,470; Peto OR, 0.89 [95% CI, 0.82 to 0.96]), and ischemic stroke by 18 percent (k=5, N=79,334; Peto OR, 0.82 [95% CI, 0.72 to 0.92]) with no differences in CVD mortality (k=11, N=134,470; Peto OR, 0.95 [95% CI, 0.86 to 1.05]) or all-cause mortality (k=11, N=134,470; Peto OR 0.98 [95% CI, 0.93 to 1.03]). Absolute risk reductions in major CVD events in the trials ranged from 0.08 to 2.5 percent. Aspirin’s benefits were similar when trials of all doses were pooled. Sensitivity analyses restricted to more recent trials where usual care includes aggressive risk factor modification including statin therapy show diminished effects of aspirin for major CVD events and total MI but larger effects for total ischemic stroke compared to older trials. A small subset of the trials reporting CVD outcomes also reported CRC outcomes. Based on 4 low-dose aspirin trials (N=86,137) recruiting primary CVD prevention populations, there was no statistically significant association between aspirin and CRC incidence when analyzing randomized trial periods (Peto OR 1.07 [95% CI, 0.92 to 1.24]; trial period 5-10 years). Analysis including post-trial observation periods up to 20 years and including trials with high-dose aspirin up to 500 mg/day (k=2; N=45,015) in primary prevention populations show statistically significant reductions in CRC incidence (0.70 [95% CI, 0.50 to 0.98] and 0.82 [95% CI, 0.69 to 0.98]). Two low-dose aspirin RCTs (N=59,020) in primary CVD prevention populations report CRC mortality during the trial period (5-10 years) showing results concerning for possible harm with one trial demonstrating a statistically significant increase in CRC mortality in older adults. At 18 years of followup, including post-trial observational periods, three primary CVD prevention trials with mean daily aspirin doses ranging from 75 to 500 mg showed aspirin was associated with a decreased risk of CRC mortality (Peto OR 0.76 [95% CI, 0.62 to 0.94]). Low-dose aspirin is associated with a 31 percent increase in intracranial bleeding events (k=11; N=134,470; Peto OR, 1.31 [95% CI, 1.11 to 1.54]), and 53 percent increase in extracranial bleeding events (k=10; N=133,194; Peto OR 1.53 [95% CI, 1.39 to 1.70]). The absolute increases ranged from −0.2 to 0.4 percent for intracranial bleeding events and 0.2 to 0.9 percent for extracranial bleeding events. There is no compelling evidence to suggest that aspirin has a different relative CVD benefit or bleeding risk in specific populations defined by age, sex, race and ethnicity, diabetes status, or baseline 10-year CVD risk. Aspirin’s CVD benefits appear to begin within the first 1-2 years of administration and the bleeding harms begin soon after aspirin initiation; there are limited data for more precise time increments or longer durations., Limitations: Primary CVD prevention trials used different aspirin doses in heterogeneous populations with relatively short study followup, with duration mostly ranging from 4-6 years. Trials reporting CRC incidence and mortality outcomes are limited by short trial duration and multiple comparisons; observational followup of trials are limited by heterogeneity of aspirin doses, duration, indications, and populations with risk of biases and confounding. Estimates of rare bleeding harms are imprecise., Conclusions: In primary prevention populations, low-dose aspirin reduces major CVD events, MI and ischemic stroke, but also increases major GI bleeding, extracranial bleeding, and intracranial bleeding. Our evidence suggests aspirin is associated with a possible long-term reduction in CRC incidence and mortality based on post-trial period observation, but the results are limited for low-dose aspirin among primary CVD prevention populations. More precise real-world U.S.-based estimates for bleeding events in the general population and specific populations with elevated CVD risk are necessary to accurately estimate the net benefit. Depending on CVD risk, this absolute CVD benefit in specific populations could potentially outweigh the bleeding risks. Models to identify these populations are needed.

Objective: We conducted this systematic review to support the U.S. Preventive Services Task Force (USPSTF) in updating its recommendation on screening for hypertension in adults. This systematic review addresses the benefits and harms of screening for hypertension in adults, including the accuracy of initial office-based screening measurements during a single encounter and confirmatory blood pressure measurements using various modalities in those who initially screen positive., Data Sources: We performed a search of MEDLINE, PubMed (publisher-supplied records only), the Cochrane Collaboration Registry of Controlled Trials, and the Cumulative Index of Nursing and Allied Health for relevant English-language studies published between February 2014, and August 2019. Additionally, we re-evaluated all studies included in the 2014 USPSTF review. We supplemented searches by examining bibliographies from retrieved articles and consulting outside experts. We searched clinical trial registries for ongoing and/or unpublished trials. We conducted ongoing surveillance for relevant literature through March 26, 2021., Study Selection: Two investigators independently reviewed 21,741 abstracts and 544 full-text articles against a set of a priori inclusion and quality criteria. Resolution of disagreements was achieved through discussion with a third reviewer. We included the following study designs: randomized controlled trials (RCTs) and clinical controlled trials (CCTs) for effectiveness of screening (KQ1); test accuracy studies for accuracy of initial office-based blood pressure screening (KQ2) and subsequent confirmatory blood pressure measurements (KQ3) using an ambulatory blood pressure measurement (ABPM) reference standard; and RCTs, CCTs, and cohort and cross-sectional studies for screening and confirmation harms (KQ4)., Data Analysis: One investigator abstracted data into evidence tables and a second investigator checked accuracy. We qualitatively synthesized data separately for each key question. We meta-analyzed study results for Key Questions 2 and 3. Our quantitative analyses utilized a bivariate model for sensitivity and specificity outcomes. We used visual inspection of forest plots arranged by various study, population, and test characteristics to explore heterogeneity., Results: For KQ1, one community-based cluster RCT (N=140,642) of a multicomponent CVD health promotion program that included hypertension screening as the primary intervention for older adults reported a 9 percent relative reduction in composite CVD-related hospital admissions (rate ratio 0.91 [95% CI, 0.86 to 0.97]). For KQ2, meta-analysis of 15 studies (N=11,309) of office-based blood pressure measurement (OBPM) for screening at a single visit demonstrated a pooled sensitivity of 0.54 (95% CI, 0.37 to 0.70) and a pooled specificity of 0.90 (95% CI, 0.84 to 0.95) with considerable clinical and statistical heterogeneity. For KQ3, 18 studies (N=57,128) of various confirmatory blood pressure measurement modalities reported data that allowed accuracy calculations; these studies used confirmation modalities of: OBPM, home blood pressure measurement (HBPM), self-OBPM (measurement performed by a patient in the office setting), and truncated ABPM. Meta-analysis of eight OBPM confirmation studies (N=53,183) showed a pooled sensitivity of 0.80 (95% CI, 0.68 to 0.88) and a pooled specificity of 0.55 (95% CI, 0.42 to 0.66) with considerable clinical and statistical heterogeneity. Meta-analysis of four HBPM confirmation studies (N=1,001) showed a pooled sensitivity of 0.84 (95% CI, 0.76 to 0.90) and a pooled specificity of 0.60 (95% CI, 0.48 to 0.71) with considerable statistical heterogeneity. Two studies of self-OBPM (N=698) and one study of truncated ABPM (N=263) provided a limited evidence base for determination of accuracy for these modalities. There was limited information about the accuracy of protocol variations, precluding conclusions about the optimal protocol characteristics for screening and confirmatory blood pressure measurement in the included studies. For KQ4, 13 studies (N=5,150) suggest that screening is associated with no decrements in quality of life or psychological distress and scant evidence on screening’s effect on absenteeism is mixed. ABPM followup testing is associated with minor adverse events including temporary sleep disturbance and bruising., Limitations: The literature identified for blood pressure screening and confirmation accuracy represented a heterogeneous group of studies resulting in inconsistent and imprecise accuracy estimates. The included protocol characteristics for screening and confirmatory blood pressure measurements likely represent “research quality” measures not followed in current practice., Conclusions: Blood pressure screening at a single visit has a low sensitivity and adequate specificity for detection of hypertension, leading to a substantial number of potentially missed cases. Confirmatory office or home blood pressure measurement applied to a population with a previously elevated blood pressure has adequate sensitivity and low specificity suggesting that these modalities may not be appropriate replacements for ABPM for diagnostic confirmation. Scant literature is available to inform best practices in blood pressure measurement to optimize test accuracy. Limited available evidence on the direct harms of screening and confirmatory blood pressure measurements suggest that the harms are minimal, and the most notable harm of blood pressure screening is likely misdiagnosis with ensuant under or over-treatment. Future research is needed to identify optimal blood pressure measurement protocols and confirmation algorithms—including blood pressure threshold values—to inform clinical practice.

Objective: To perform a targeted systematic review of evidence regarding the benefits and harms of screening for asymptomatic carotid artery stenosis in the general population to support the update of the USPSTF’s 2014 D recommendation for this topic., Data Sources: We conducted a literature search of MEDLINE, PubMed Publisher-Supplied Records, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1, 2014, to February 14, 2020. In addition, we conducted ongoing surveillance of relevant literature through November 20, 2020., Study Selection: We screened 2,374 abstracts and 144 full-text articles against a priori inclusion criteria. Retrospective analyses of vascular surgical registries were limited to data collected in the United States., Data Analysis: Working independently, two investigators critically appraised each article that met inclusion criteria using design-specific criteria. We abstracted and narratively synthesized data from included studies. The results discussed in this report are limited to studies published since the previous review to support the 2014 recommendation., Results: No eligible studies were identified that directly examined the benefits or harms of screening for asymptomatic carotid artery stenosis. Since the last USPSTF recommendation on this topic, two limited, fair-quality, prematurely terminated trials reported mixed results for the comparative effectiveness of carotid revascularization (carotid endarterectomy [CEA] or carotid artery stenting [CAS]) plus best medical treatment (BMT) compared with BMT alone. The SPACE-2 trial (N=316 reported no difference in composite outcome of stroke or death (30 days) or ipsilateral ischemic stroke (1 year) after CEA (unadjusted hazard ratio [HR] 2.82 [95% CI, 0.33 to 24.07]) or CAS (unadjusted HR 3.50 [95% CI, 0.42, 29.11]) compared with BMT in the 1-year interim publication. The smaller AMTEC trial (N=55) reported a statistically significantly lower composite risk of nonfatal ipsilateral stroke or death among the carotid endarterectomy (CEA) arm at 3.3 median years of followup (calculated unadjusted HR 0.20 [95% CI, 0.06 to 0.65]). Since the previous report, two fair-quality trials, two national datasets, and three surgical registries met our inclusion criteria reporting harms associated with CEA (N=1,903,761) or carotid artery stenting (CAS) (N=332,103). Overall, the rates of most postoperative adverse events were highest among analyses of national databases (Medicare data and National Inpatient Sample [NIS]), with lower rates reported in trials and surgical registries. Within the national databases and surgical registries, rates of 30-day postoperative stroke or death following CEA ranged from as low as 1.4 percent in the Vascular Quality Initiative (VQI) to as high as 3.5 percent in the Medicare database. Thirty-day postoperative mortality ranged from 0.5 percent in the Vascular Study Group of New England (VSGNE) to as high as 1.1 percent in the Medicare database for CEA. Thirty-day postoperative stroke rates following CEA ranged from 0.5 percent in the VSGNE to 1.5 percent in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). For the CAS procedure, 30-day stroke or death ranged from 2.6 percent in the VQI to 5.1 percent in Medicare. Thirty-day postoperative mortality after CAS ranged from 1.1 percent in the VQI to 3.1 percent in the Medicare database. Thirty-day postoperative stroke rates following CAS were only reported in the VQI at 1.8 percent. Rates of postoperative harms within the trials were generally underpowered to detect outcomes such as postoperative mortality. Within the SPACE-2 trial, the composite of 30-day postoperative stroke or death was reported at 2.5 percent following both CAS and CEA. Perioperative stroke was reported in one patient (3.2%) following CEA in the AMTEC trial. The other most common harms reported within trials included hematoma, facial nerve lesion, and contrast agent incompatibility., Limitations: We identified no trials of screening versus no screening in unselected general populations or examining direct screening harms. There were few new trials, all with methodologic concerns, examining the important question of the comparative effectiveness and harms of revascularization plus best medical treatment compared with best medical treatment alone. Selection bias and measurement bias presented serious validity concerns for complication rates reported in the administrative databases and surgical registries. The procedural complication rates of patients categorized as “asymptomatic” in the harms studies may not be generalizable to the rates that may be expected in a population of screen-detected patients (who would be expected to have lower complication rates compared with populations with any neurologic symptoms or remote history of TIA or stroke) or procedures performed outside of trials by less-selected operators (who may be expected to have higher complication rates compared with highly selected operators at high volume centers)., Conclusions: There are no population-based screening trials addressing the benefits and harms of screening for carotid artery stenosis. Limited new evidence has emerged to determine the benefits of carotid revascularization over contemporary best medical management in asymptomatic patients. The ongoing CREST-2 and ECST-2 trials will be the largest trials to address this issue. Large national administrative databases and surgery registries suggest that postoperative 30-day stroke/death rates vary widely—1.4 to 3.5 percent for CEA and 2.6 to 5.1 percent for CAS—suggesting that there may be a wide variation in complication rates likely attributable to patient and operator selection.

Objective: To systematically review evidence about the benefits and harms of ultrasound-based abdominal aortic aneurysm (AAA) screening and small aneurysm treatment in primary care populations, including subpopulations of older adults, women, smokers, racial/ethnic subgroups, and those with a family history of AAA., Data Sources: We performed a search of MEDLINE, PubMed (Publisher Supplied only), the Database of Abstracts of Reviews of Effects, and the Cochrane Collaboration Registry of Controlled Trials for relevant English-language studies published between January 2012 and September 14, 2018. Additionally, we re-evaluated all studies included in the 2014 USPSTF review. We supplemented searches by examining bibliographies from retrieved articles and consulting outside experts. We searched Federal Agency trial registries for ongoing and/or unpublished trials., Study Selection: Two investigators independently reviewed identified abstracts and full-text articles against a set of a priori inclusion and quality criteria. Resolution of disagreements occurred through discussion with a third reviewer. We included the following study designs: randomized, controlled trials (RCTs) for the effectiveness of screening and small aneurysm treatment interventions; RCTs and large cohort studies for rescreening effectiveness and screening/rescreening harms; and RCTs, large cohort studies, and vascular survey registries for small aneurysm treatment harms., Data Analysis: One investigator abstracted data into evidence tables and a second investigator checked accuracy. We qualitatively synthesized the data for each Key Question and performed meta-analyis on trial results for Key Questions 1 and 3. Our analyses utilized the Peto method to pool odds ratios (ORs) (for AAA-related mortality, rupture, and operations) and the DerSimonian and Laird random-effects model to pool calculated risk ratios (for all-cause mortality). Subgroup-specific results were abstracted and qualitatively synthesized from any included studies reporting outcomes for our a priori list of subgroups., Results: Based on four fair- to good-quality, population-based RCTs (N=124,929), the invitation for screening men age 65 years or older was associated with a 35 percent reduction in AAA-related mortality and a 38 percent reduction in AAA rupture rate; screening was also associated with a 43 percent reduction in the number of emergency surgeries. There was no statistically significant difference, however, in all-cause mortality at 12- to 15-year followup. Based on eight heterogeneous, short-term rescreening studies (N=8,018) with a variety of protocols (rescreening annually to 5 years, with a total of one to six repeated scans), AAA-related mortality up to 5 to 12 years appears to be rare (<3%) among persons with normal aortas (<3 cm) on the initial scan. Upon rescreening, few aortas (0% to 2.2%) expanded to larger than 5 cm at 5 years and 0 to 15 percent had progressed at 10 years. One-time screening is associated with a nearly 44 percent more surgeries in the invited group compared to the control group (K=5; N=175,085; Peto OR, 1.44 [95% CI, 1.34 to 1.55]), largely driven by elective operations (Peto OR, 1.75 [95% CI, 1.61 to 1.90]). There was no statistically significant difference in 30-day mortality rates in the invited vs. control groups for either elective surgeries or emergency surgeries at the 12- to 15-year followup. Five studies generally showed no significant long-term differences in quality of life, anxiety, and depression scores between persons who screen positive and those who screen negative up to 12 months. Four fair- to good-quality studies (N=3,314) of small aneurysm (4.0 to 5.4 cm) treatment demonstrate that endovascular repair (EVAR) and open repair are associated with no difference in AAA-related mortality or all-cause mortality compared to surveillance. Early open repair, however, was found to significantly reduce the rate of rupture compared to surveillance. These four trials show an approximately 50 to 100 percent increase in procedures in the early surgery group and no difference in 30-day mortality rates. Complications such as cardiac, pulmonary, and renal events reported in registry databases were generally comparable to those reported in the trials, with the exception of reintervention rates for open repair, which were higher in the registries than in the open trial reporting this outcome. Seven fair-quality, short-term drug trials (N=1,553) of antibiotics, antihypertensive medications, and mast cell stabilizers showed no overall effect on AAA growth compared to placebo. Propranolol trials, however, reported high withdrawals due to adverse events, but other drugs appear to be well tolerated. There are limited data on screening effectiveness or harms in subpopulations; outcomes were rarely reported by subpopulation and when available, the data are full of methodologic limitations. For small aneurysm treatment, available evidence from registry data (k=3; N=14,424) shows that women have higher surgical complications and postoperative mortality compared to men. Two trials reported no differences in all-cause mortality associated with open surgical repair of small aneurysm by age, sex, or smoking history., Limitations: Trials included mostly white men outside of the United States. Information for subgroups and about rescreening was limited., Conclusions: A one-time invitation for AAA screening in men age 65 years or older was associated with decreased AAA-related mortality and rupture rates but had little or no effect on all-cause mortality. Screening is associated with higher rates of elective surgery, but there are no long-term differences in the quality of life in persons who screen positive. Treatment of small, screen-detected AAA with early open or EVAR surgery did not result in improved health outcomes compared to surveillance but result in more elective surgeries. There are limited data on pharmacotherapy treatment of small aneurysms showing no statistically significant effect on AAA growth rates. There are limited data on screening effectiveness or harms in subpopulations; small aneurysm surgical complication rates appear to be greater in women than in men.

Objective: To systematically review evidence regarding the benefits and harms of ocular prophylaxis for the prevention of gonococcal ophthalmia neonatorum to support the update of the USPSTF’s 2011 A recommendation for this topic., Data Sources: We conducted a literature search of PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1, 2008, to January 16, 2018., Study Selection: We screened 282 abstracts and 6 full-text articles against a priori inclusion criteria. We included studies conducted in countries categorized as “high” or “very high” on the Human Development Index., Data Analysis: Two investigators independently critically appraised each article that met inclusion criteria using design-specific criteria., Results: No new eligible studies were identified., Limitations: Our review was designed to identify evidence that could result in a change in the 2011 USPSTF recommendation; therefore, it targeted only those studies in countries categorized as high or very high on the Human Development Index., Conclusions: Ocular prophylaxis for the prevention of gonococcal ophthalmia neonatorum is the standard of care in the United States. Foundational evidence in support of this practice included largely observational studies from developing countries over 2 decades ago demonstrating substantial reductions in GON incidence associated with prophylaxis. Our brief evidence update found no new evidence of the benefits or harms of ocular prophylaxis for gonococcal ophthalmia neonatorum.