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Importance Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. Objective To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. Design, Setting, and Participants Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible. Interventions Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons. Main Outcomes and Measures The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed. Results Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17];P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants. Conclusions and Relevance In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population. Trial Registration ClinicalTrials.gov Identifier:NCT02787044

WILLIAM HARVEY, THE 17TH-CENTURY ENGLISH physician who first correctly described how the heart pumped blood around the body, was quoted as saying, “All we know is still infinitely less than all that remains unknown.” To his credit and humility, he understood that his work only set the stage for many discoveries yet to come. All physicians could learn important lessons from Harvey. Looking back to past research can provide interesting insights into how the field of cardiovascular medicine got to where it is and also important hints on where it may be going. Yet historical reviews can also be humbling, demonstrating how prior generations had inaccurately interpreted their findings and in other cases, how slow clinicians have been in adopting past advances. It is therefore appropriate that JAMA’s 2012 cardiovascular disease theme issue includes “The Resuscitation of the Heart,” an editorial originally published 100 years ago. The article describes how experiments using cardiac massage and electrical stimulation in dogs had shown promise in bringing animals back from the dead. The results seemed miraculous to the authors owing to their rudimentary understanding of cardiac physiology, yet they still foresaw the future of cardiopulmonary resuscitation (CPR) and cardiac defibrillator therapy in humans. It would be another 35 years, however, before the first successful defibrillation of an exposed human heart was performed; another 45 years until the first closed chest cardiac defibrillators came to routine use; and nearly 70 years until the first implantable defibrillator device would reach the market. Perhaps most concerning, even today, only a small proportion of the US population has received CPR training, cardiac defibrillator response time even in hospitals is far from ideal, and only up to two-thirds of patients eligible for an implantable defibrillator actually receive the device. Certainly in these cases, the translation of experimental concepts to routine cardiology practice has been less than ideal in these cases. In this theme issue of JAMA, readers can view some of the latest contemporary cardiovascular discoveries. Three epidemiological studies examine the prevalence of cardiac risk factors and their association with clinical events in various populations. It may seem remarkable that more than 50 years after the basic cardiac risk factors were first described there is more to say, yet each of these latest contributions provides important, novel insights. In one report, Wilkins and colleagues use nearly 1 million person-years of follow-up data from large cohort studies to estimate lifetime risk of cardiovascular disease (CVD). Their study found that the lifetime odds for CVD are proportional to the number of cardiac risk factors. Importantly, those with an “optimal” risk factor profile at midlife have a several-fold lower lifetime likelihood for cardiac events compared with those with multiple risk factors. Many of the major cardiac cohort studies to date were conducted in predominantly white populations, and they thus fail to reflect the racial and ethnic diversity of the United States. Studying a broad, racially diverse cohort, Safford and colleagues address this epidemiological gap and find that both black men and black women have a nearly 2-fold higher risk for fatal cardiac events relative to their white peers. However, the study also points out that these differences reflect the high burden of cardiac risk factors seen in black patients. An additional article by Daviglus and colleagues identifies similar issues among those of Hispanic origin. This report is the first major publication from the Hispanic Community Health Study/Study of Latinos, a very large National Institutes of Health–sponsored initiative to characterize CVD in diverse US Latino populations. The researchers note the high burden of cardiac risk factors in Latino populations, particularly among those of Puerto Rican origin, lower socioeconomic background, and more acculturation into the US lifestyle. Taken together, these 3 articles highlight the pressing need (and incredible opportunity) for primary and secondary prevention interventions to reduce CVD death and disability among all racial/ethnic groups in the United States. Beyond epidemiology, cardiovascular medicine also advances through direct human experimentation. Randomized clinical trials (RCTs) provide ideal tools to confirm (or

THE HEART HAS ALWAYS HELD A SPECIAL FASCINATION for humans: it has been the seat of the soul; the home of emotions; and the pump that when beating, symbolizes life, and when silent, signifies death. Perhaps no other organ in the body has been so closely scrutinized. Therefore it is appropriate that as scientists and clinicians from around the globe gather at the 2011 American Heart Association (AHA) Scientific Sessions, we devote this theme issue of JAMA to cardiovascular disease (CVD). It is our hope that readers will clearly see that cardiovascular medicine remains a vital and rapidly changing discipline, filled with innovation yet also confronting significant challenges. Only 50 years ago, atherosclerosis was thought to be inevitable, a natural consequence of the aging process. However, carefully performed epidemiologic studies from the Framingham Heart Study and others identified the major CVD risk factors including hypertension, elevated cholesterol levels, smoking, and diabetes. These seminal works changed the view of CVD from a preordained fate to a preventable disorder. Much has been learned since that time regarding the etiology of CVD, yet multiple mysteries persist. For example, although the onset of CVD is directly related to the burden of CVD risk factors, Canto and colleagues, in their report in this issue of JAMA, found, paradoxically, that inhospital mortality following an initial myocardial infarction (MI) was inversely associated with the number of baseline risk factors. This interesting finding either could represent residual confounding or may indicate that patients without traditional risk factors who have an acute coronary event may harbor novel but as-yet uncharacterized and deadly CVD risk factors. Another “known but unknown” in CVD risk centers on blood pressure. Although it is known that high blood pressure can lead to CVD and stroke, the optimal therapeutic target for blood pressure control remains unclear. In their study of patients following a stroke, Ovbiagele and colleagues found a U-shaped association between longitudinal blood pressure levels and risk for recurrent events. The higher risk at lower levels of blood pressure could be the result of residual confounding, but these observational data raise the possibility that there may be harm if blood pressure management is too aggressive or too lenient. Cholesterol management is another important and modifiable risk factor. Scientists have unraveled the complexities of cholesterol metabolism and identified several therapeutic targets for manipulation. Statins effectively lower low-density lipoprotein (LDL) cholesterol levels and subsequently reduce CVD events when used in select primary and secondary populations. In this issue of JAMA, Nicholls and colleagues report on the first large experience with evacetrapib, a novel, potent, and selective inhibitor of cholesteryl ester transfer protein (CETP). In their clinical trial, the authors found that this new drug, when added to a statin regimen, further favorably improved lipid profiles by not only decreasing LDL levels but also by substantially increasing high-density lipoprotein (HDL) cholesterol levels. Although these findings are promising, subsequent larger outcome trials will be needed to confirm that these modifications in lipid profile translate into lower long-term CVD risk. The past few decades have seen the emergence of a number of acute and chronic interventions that prevent events, improve the quality of life, and save lives for patients with CVD. The tradition of exploration of novel concepts in CVD therapy continues in the research on the potential for pleuripotent stem cells to repair and replace damaged myocardium. To date, animal models have demonstrated that stem cell infusions following experimental infarction can restore ventricular function, yet the role of this intervention in humans remains controversial. In this issue, Traverse and colleagues report the primary findings of the LateTIME trial, the first of a series of human clinical stem cell trials sponsored by the National Heart, Lung, and Blood Institute (NHLBI). Their clinical trial was designed to specifically address the optimal timing of stem cell

Context The lifetime risk of heart failure at age 40 years is approximately 1 in 5 in the general population; however, little is known about the association between modifiable lifestyle factors and the remaining lifetime risk of heart failure. Objective To examine the association between modifiable lifestyle factors and the lifetime risk of heart failure in a large cohort of men. Design, Setting, and Participants Prospective cohort study using data from 20 900 men (mean age at baseline, 53.6 years) from the Physicians' Health Study I (1982-2008) who were apparently healthy at baseline. Six modifiable lifestyle factors were assessed: body weight, smoking, exercise, alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables. Main Outcome Measure Lifetime risk of heart failure. Results During a mean follow-up of 22.4 years, 1200 men developed heart failure. Overall, the lifetime risk of heart failure was 13.8% (95% confidence interval [CI], 12.9%-14.7%) at age 40 years. Lifetime risk remained constant in men who survived free of heart failure through age 70 years and reached 10.6% (95% CI, 9.4%-11.7%) at age 80 years. Lifetime risk of heart failure was higher in men with hypertension than in those without hypertension. Healthy lifestyle habits (normal body weight, not smoking, regular exercise, moderate alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables) were individually and jointly associated with a lower lifetime risk of heart failure, with the highest risk in men adhering to none of the 6 lifestyle factors (21.2%; 95% CI, 16.8%-25.6%) and the lowest risk in men adhering to 4 or more desirable factors (10.1%; 95% CI, 7.9%-12.3%). Conclusion In this cohort of apparently healthy men, adherence to healthy lifestyle factors is associated with a lower lifetime risk of heart failure.

Context Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer. Objective To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men. Design, Setting, and Participants The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14 641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled. Intervention Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily. Main Outcome Measures Prostate and total cancer. Results During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk. Conclusions In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men. Trial Registration clinicaltrials.gov Identifier: NCT00270647Published online December 9, 2008 (doi:10.1001/jama.2008.862).

Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials.To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD.Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005.Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12.A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality.Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years vs 39.5/10,000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10,000 person-years vs 36.8/10,000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10,000 person-years vs 49.6/10,000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P.001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95% CI, 1.54-2.96 micromol/L).After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.clinicaltrials.gov Identifier: NCT00000541.

Migraine with aura has been associated with an adverse cardiovascular risk profile and prothrombotic factors that, along with migraine-specific physiology, may increase the risk of vascular events. Although migraine with aura has been associated with increased risk of ischemic stroke, an association with cardiovascular disease (CVD) and, specifically, coronary events remains unclear.To evaluate the association between migraine with and without aura and subsequent risk of overall and specific CVD.Prospective cohort study of 27,840 US women aged 45 years or older who were participating in the Women's Health Study, were free of CVD and angina at study entry (1992-1995), and who had information on self-reported migraine and aura status, and lipid measurements. This report is based on follow-up data through March 31, 2004.The primary outcome measure was the combined end point of major CVD (first instance of nonfatal ischemic stroke, nonfatal myocardial infarction, or death due to ischemic CVD); other measures were first ischemic stroke, myocardial infarction, coronary revascularization, angina, and death due to ischemic CVD.At baseline, 5125 women (18.4%) reported any history of migraine; of the 3610 with active migraine (migraine in the prior year), 1434 (39.7%) indicated aura symptoms. During a mean of 10 years of follow-up, 580 major CVD events occurred. Compared with women with no migraine history, women who reported active migraine with aura had multivariable-adjusted hazard ratios of 2.15 (95% confidence interval [CI], 1.58-2.92; P.001) for major CVD, 1.91 (95% CI, 1.17-3.10; P = .01) for ischemic stroke, 2.08 (95% CI, 1.30-3.31; P = .002) for myocardial infarction, 1.74 (95% CI, 1.23-2.46; P = .002) for coronary revascularization, 1.71 (95% CI, 1.16-2.53; P = .007) for angina, and 2.33 (95% CI, 1.21-4.51; P = .01) for ischemic CVD death. After adjusting for age, there were 18 additional major CVD events attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura did not have increased risk of any vascular events or angina.In this large, prospective cohort of women, active migraine with aura was associated with increased risk of major CVD, myocardial infarction, ischemic stroke, and death due to ischemic CVD, as well as with coronary revascularization and angina. Active migraine without aura was not associated with increased risk of any CVD event.

Withmore than 100yearsofuse, aspirin is oneof themost extensively studied drugs in the history of medicine. In addition to its analgesic, anti-inflammatory, and antipyretic effects, acetylsalicylic acid is a potent irreversible inhibitor of platelet aggregation. In the late 19th century the acetylation of salicylic acid in an attempt tomake it less bitter and hence more palatable inadvertently gave this compound a unique property—the acetyl group can be transferred to the serine residue in theactive site of theenzymecyclooxygenase (COX), irreversibly inhibiting its function and therebypreventing the production of prostaglandins. In certain cells this property of aspirin is responsible for analgesic, anti-inflammatory, andantipyretic effects. Inplatelets, theCOX-1 isoformproduces thromboxaneA2,which aids in platelet aggregation. Thus, aspirin inhibits platelet aggregationandcan reduce thrombosis. In cellswithanucleus,COX canbe regenerated. Because platelets havenonucleus, COX-1 cannotbe reproducedand ispermanently inhibited.This leads to a prolonged antithrombotic effect lasting several days after a single dose until enough new platelets have been produced to restore normal function of the thrombotic system. With thisuniqueproperty, aspirinhasvaluable therapeutic effects inreducingtheriskofarterialvascularthromboticevents, suchasmyocardial infarctionandstroke,and, toa lesserextent, venous thrombotic events.However, this actionof aspirin also increases the risk of bleeding, leading to itsmost troubling adverseeffects: seriousgastrointestinalbleedingandhemorrhagic stroke.Overall, the balance betweenbenefit in preventingmajor vascular events and the risk of increasing serious bleeding events underlies the clinical decision ofwhen to use this inexpensivegenericdrug. Ingeneral, thehigher the riskof vascular events, themore advantageous it is to prescribe aspirin. A single trial, ISIS-2,1 demonstrated theutility of daily aspirin inthesettingofacutemyocardial infarctionreducingtherisk of vascular death by 23%.Aspirin also has been shown to be effectiveinthesettingofacuteischemicstroke.2Theacutebenefits of aspirin inaiding in thedissolutionof anacute thrombusover hourstodaysandthusrestoringbloodflowinthesettingofstroke ormyocardial infarctionvastlyoutweighanyshort-termbleedingrisks.For this reason,aspirin isamainstayofearly therapy in the acute settings of acute coronary syndromes and stroke. In pooled data from about 200 trials among patients with knownvascular disease, aspirinwas shown tohave long-term benefits inpreventingmajorvascularevents.2These trialsdemonstrated that among thosewithknownvasculardisease there isnetbenefit, reducingtheriskofmajorvasculareventsbymore than 20%exceeding themodest bleeding riskswhenaspirin is takenat a lowdosedaily.Higherdosesdonot increase thebeneficial effects but increase the risk of bleeding. Thus, aspirin is recommended at a dose of 75mg to 100mgper day for longertermsecondarypreventionofcardiovascularevents inpatients withknownvasculardisease.Aspirin alsohasutility in the settingof vascular procedures suchaspercutaneous coronary interventions,reducingtheriskofrestenosis,andisrecommended for several months up to a year after the procedure. Given thebeneficial effects of aspirinduring acute events, followingprocedures, and in the secondarypreventionofmajor vascular events among patients with cardiovascular disease (CVD), itwas logical to askwhether this inexpensivedrug could prevent the firstmyocardial infarction or stroke among persons who have yet to manifest vascular disease. Primary prevention trials for this question are especially challenging given the continued reduction in the incidence of important outcomes and require very large study populations followed up for many years. Beginning in the 1980s several large-scale trials were undertaken to address this question, startingwith 2 trials among male physicians, the British Doctors’ Trial3 and the Physicians’ Health Study.4 These studies, along with a handful of other primary prevention trials among more than 100 000 studyparticipants, havegenerally shownmoremodest reductions ofmajor vascular events comparedwith secondary prevention (12% for major vascular events vs 22% for secondary prevention5,6)andreductions inmyocardial infarctionandtransient ischemic attack risk, and some have demonstrated a reduced risk of ischemic stroke.5,6 In the vast majority of the primary prevention trials, the overall risk level of CVD events was very low.5 In the primary preventionsetting, thereare limiteddataamongthoseathigher risk. There is also a paucity of data in Asian populations, in which hemorrhagic stroke risk (one of the important adverse effects of aspirin) tends to be higher than inWestern populations, and thus this population is of particular interest. In this issue of JAMA, Ikeda and colleagues7 report the results of the Japanese Primary Prevention Project (JPPP). The JPPPclinical trial studiedtheeffectofonce-daily, low-dose (100 mg), enteric-coated aspirin comparedwith no aspirin for preventing atherosclerotic events in 14 658 Japanese patients 60 years or older with hypertension, dyslipidemia, or diabetes. The study,whichhadplanned to followupparticipants for 6.5 years,was stoppedearly due to futility. After amedian follow-upof5years, therewasnosignificantdifference in the rate of the composite primary end point of total number of major atherosclerotic events (nonfatal myocardial infarction, nonOpinion

ContextPhysical inactivity and body mass index (BMI) are established independent risk factors in the development of type 2 diabetes; however, their comparative importance and joint relationship with diabetes are unclear.ObjectiveTo examine the relative contributions and joint association of physical activity and BMI with diabetes.Design, Setting, and ParticipantsProspective cohort study of 37 878 women free of cardiovascular disease, cancer, and diabetes with 6.9 years of mean follow-up. Weight, height, and recreational activities were reported at study entry. Normal weight was defined as a BMI of less than 25; overweight, 25 to less than 30; and obese, 30 or higher. Active was defined as expending more than 1000 kcal on recreational activities per week.Main Outcome MeasureIncident type 2 diabetes, defined as a new self-reported diagnosis of diabetes.ResultsDuring the follow-up, 1361 cases of incident diabetes occurred. Individually, BMI and physical activity were significant predictors of incident diabetes. Compared with normal-weight individuals, the multivariate-adjusted hazard ratio (HR) was 3.22 (95% confidence interval [CI], 2.69-3.87) for overweight individuals and 9.09 (95% CI, 7.62-10.8) for obese individuals. For overall activity (kilocalories expended per week), compared with the least active first quartile, the multivariate-adjusted HRs were 0.91 (95% CI, 0.79-1.06) for the second quartile, 0.86 (95% CI, 0.74-1.01) for the third, and 0.82 (95% CI, 0.70-0.97) for the fourth (P for trend = .01). In the combined analyses, overweight and obese participants, whether active or inactive, had significantly elevated risks, compared with normal-weight active individuals. The multivariate-adjusted HRs were 1.15 (95% CI, 0.83-1.59) for normal-weight inactive, 3.68 (95% CI, 2.63-5.15) for overweight active, 4.16 (95% CI, 3.05-5.66) for overweight inactive, 11.5 (95% CI, 8.34-15.9) for obese active, and 11.8 (95% CI, 8.75-16.0) for obese inactive participants.ConclusionsAlthough BMI and physical inactivity are independent predictors of incident diabetes, the magnitude of the association with BMI was greater than with physical activity in combined analyses. These findings underscore the critical importance of adiposity as a determinant of diabetes.

In November 2014, JAMA will publish a theme issue on cardiovascular disease, and this will mark the fourth year the theme issue will coincide with the American Heart Association Scientific Sessions.1- 3 In this issue, we hope to include articles about cardiovascular disease that are relevant to the broad readership of JAMA.

Hypertension is themost common cardiovascular risk factor in the United States, affecting approximately two-thirds of adults aged60yearsorolder.1Observational studieshavedemonstrateda linear relationshipbetweenbloodpressure (BP)and risk of cardiovascular events. Randomized controlled trials (RCTs) have found that loweringBPby as little as 10mmHg in patientswithhypertension can reduce aperson’s lifetime risk forcardiovascularandstrokedeathby25%to40%.2Yet forsuch a common and treatable condition, the ideal treatment goal remains uncertain—both overall and as a function of a patient’s age. Compared with younger patients, older patients withhypertension are at increased risk for cardiovascular and stroke events yet are more vulnerable to complications related to pharmacological treatment of hypertension. The last JointNationalCommittee (JNC7)Guideline, sponsoredbytheNationalHeart,Lung,andBlood Institute (NHLBI), was released more than a decade ago.3 The updated recommendations formanagement of high blood pressure from the panel members appointed to the JNC 8 Committee was launched 5 years ago. Theprocess used in themost recent update differed from the prior guideline by focusing on select clinical questions that were to be answered solely using evidence from RCTs. Despite this empirical approach, the panel’s summary recommendationswereultimatelynot sanctionedby the NHLBI.Thepanel’s report isnowpublished in JAMAasastandalone document,4 and it remains unclear as to whether, or when, or by whom another consensus national hypertension guideline will again be formulated. Where does this leave practitioners, patients, and policy makers? The major difference between the JNC 7 report and the current panel recommendations centers on whether target BP treatment goals should be more conservative (ie, set higher) inoldervsyoungerpopulations.Specifically, JNC7concluded that all adult patientswithhypertension (regardless of their age) should have their BP reduced to a systolic BP (SBP) of lower than 140 mm Hg, with even tighter control in patientswithdiabetesor renal disease (SBP

The prevalence and disease burden of cardiovascular disease (CVD) and thewidespread use ofmedications for its preventionand treatmenthave led to the concept that a singlepill containing several cardiovascular medications, a “polypill,” might be useful inmore effectively delivering pharmacologic interventions than the samemedicationsprescribedand taken separately. For about a decade and a half there have been active discussions of combination pills for primary or secondary prevention of CVD.1 The discussion is consistent with the widespread interest in the importance of noncommunicable diseases, particularly in lowandmiddle-income countries. The logic for the polypill seems sound. CVD is commonas are its major risk factors, and effective pharmacologic treatmentsareoftentakentogether.Combiningsomeof thesemedications into a single pill most likely will improve adherence, whichdeclineswith increasing numbers of medications, and a polypill might improvedistributionofmedication. It is alsopossible that costs could be lower because generic medications with a long history of use could be combined; for instance, several available blood pressure pills combine 2 antihypertensive medications.With this simple logic, the concept of providing combination therapy in a single pill has been embraced by prominent researchers andorganizations including theWorldHealth Organization. Yet for all the discussion, movement toward implementation has been slow. Why has what seems to be such a good idea still not been widely studied and implemented? There are several challenges tomake a successful combination pill. Technically the agents must be stable when combined. There must be no adverse interaction when the medications are taken together. Medications have to be able to be taken at the same time of the day. The combination pill might require regulatory approval. Itneeds tobeproduced,marketed,anddistributed;and itmustbeeconomically viable. This all requires substantial investment to ensure widespread uptake. Factors that could further complicate theuse of combination pills include the issue of adverse effects to one drug and theneed toproducemultiple pills if a numberof possibledose combinations are necessary. Adverse effects to one medication could result in cessation of all agents in a given polypill. Cliniciansmay not knowwhich polypill ingredient is causing the adverse effects. If just 2 doses each of 4 medications are used, 2 x 2 x 2 x 2 or 16 different dose combinationswould be needed to make all dose combinations available. Another consideration is identifying good candidates for the polypill. There are 3 settings in which this combination medication approach could beuseful. First, thepolypill could beusedbypatientswith knownCVDor those at high riskwho are already taking severalmedications, oftenat the same time. In this setting a polypill could improve medication adherence. Second, in lower-incomecountries a singlepill for either primary or secondary CVD prevention might lower cost and increase efficiencyby simultaneouslydeliveringmultiplepreventive interventions to appropriate higher-risk patientswho are not receiving these interventions. Third, the combination pill could be used to increase the number of people receiving preventive interventions if this approachwere promoted as a simpleway for those at risk for CVD to adopt an effective preventive intervention.WaldandLaw2havesuggested thatusing a polypill in everyone older than about 55 years for primary prevention could reduce CVD bymore than 80%. Many formulations for a CVD polypill have been proposed. Because hypertension and dyslipidemia are common and often coexist, most combinations contain at least 1 blood pressuremedicationand1 statin. Somecombinationagents include aspirin, andothers have suggested including certain vitamins and minerals. While there have been many proposed polypill combinations andseveral settings inwhich theycould be used, randomized trial data of specific polypills in specific settings are limited. Several short-term, randomized trials3-7 have evaluated variouspolypills containing from1to3antihypertensiveagents and a statin and some contained aspirin. These trialswere designed to determine the magnitude of change in blood pressure or lipid levels and whether this magnitude was consistent with what would be expected based on trials of single agents. When compared with placebo, the combination pills resulted in meaningful reductions in systolic and diastolic bloodpressure, and in total and low-density lipoprotein (LDL) cholesterol, but these reductions were less than what would have been expected from the component medications based on trials of these agents taken as single medications.8 In this issue of JAMA, Thom and colleagues,9 representing a group of international investigators, evaluated the utility of a polypill strategy in 3 European countries and India for deliveringmedication to patients with CVD or at high risk for CVDevents by presence ofmultiple risk factors. The 2004patientswere takingmultiplemedications for hypertension and dyslipidemiaprior to enrollment. In this randomized trial, the polypill group was given a combination of 2 blood pressure medications (lisinopril 10 mg, atenolol 50 mg), 1 lipidloweringmedication (simvastatin40mg), andaspirin (75mg), while the usual care group continued individual medication intake as per usual. Comparedwith patients in the usual care group, those in thecombinationpill grouphad improvedmedicationadherenceandmodest reductions inbloodpressure (2.6 Related article page 918 Opinion

Dr Wang and colleagues note that several factors that may alter the risk of cancer were not listed in the baseline table in our article, such as diabetes and use of statins and antidiabetic drugs. This population was healthier than the general population, as demonstrated by the low smoking rates

Context Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality. Objective To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men. Design, Setting, and Participants A large-scale, randomized, double-blind, placebo-controlled trial (Physicians' Health Study II) of 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011. Intervention Daily multivitamin or placebo. Main Outcome Measures Total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points. Results During a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1000 person-years; hazard ratio [HR], 0.92; 95% CI, 0.86-0.998; P = .04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1000 person-years; HR, 0.98; 95% CI, 0.88-1.09; P = .76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1000 person-years; HR, 0.89; 95% CI, 0.68-1.17; P = .39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1000 person-years; HR, 0.88; 95% CI, 0.77-1.01; P = .07). Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56-0.96; P = .02), but this did not differ significantly from that among 13 329 men initially without cancer (HR, 0.94; 95% CI, 0.87-1.02; P = .15; P for interaction = .07). Conclusion In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer. Trial Registration clinicaltrials.gov Identifier: NCT00270647

OVER THE PAST CENTURY AS THE WEST TRANSItioned from an agrarian to an industrial economy, the nature of the dominant diseases afflicting humans changed from communicable to chronic conditions. During this epidemiologic transition, cardiovascular disease has ascended from an uncommon problem to its current position as the number one cause of death and disability worldwide. This transformation of human disease is continuing as regional economies develop and the global population ages. In many highincome countries the onset of some cardiovascular events is being delayed from middle to older age and more people are living longer with various forms of cardiovascular disease. In middleand lower-income countries the ascendancy of cardiovascular disease has been more rapid than in the West. Although some progress has been made in parts of the world in reversing trends in certain cardiovascular risk factors, major risk factors such as obesity are still on the rise globally. The emergence of this cardiovascular disease epidemic has led to amazing advances in understanding of its pathophysiology and improvements in treatment. Health care systems have evolved to deal with acute manifestations of chronic diseases, such as myocardial infarction and stroke, improving survival and lessening disability. Secondary preventive strategies such as -blockers and angiotensin-converting enzyme inhibitors have improved long-term management. Preventive and public health measures (eg, diet modification and exercise) have reduced the rates of incident myocardial infarction and stroke in the West. However, the challenges to deal with this global burden of risk factors and cardiovascular disease remain substantial. In November, as clinicians and scientists gather to exchange information and ideas about virtually all aspects of cardiovascular disease at the American Heart Association’s Scientific Sessions, JAMA will publish a theme issue on cardiovascular disease. We at JAMA view this as an opportunity to share with our worldwide readers, listeners, and viewers important new findings on understanding of cardiovascular disease as well as of major challenges and future directions in its prevention, treatment, and longer-term management. As we plan for this theme issue, authors are invited to submit manuscripts on any topic related to cardiovascular disease for consideration for this JAMA theme issue. A high priority will be given to manuscripts reporting results of major late-breaking clinical trials and other high-impact studies that will be presented at the American Heart Association’s Scientific Sessions. These will be considered for simultaneous release at the time of the presentation. We are interested in high-quality clinically relevant original research that includes multicenter randomized trials and large-scale observational epidemiological studies. We also welcome scholarly work addressing how to expedite the adoption of effective cardiac therapies into clinical settings. Manuscripts on comparative effectiveness, application of cardiovascular disease treatments in clinical settings, prevention, and novel work that expands understanding of the mechanistic underpinnings of cardiovascular disease will be considered. The effect of cardiovascular disease around the globe is also important to our readers. Interested authors should consult the Instructions for Authors for guidelines on preparation and submission of manuscripts. All submitted manuscripts will undergo JAMA’s usual rigorous editorial review and evaluation. Manuscripts received by July 1, 2012, will have the best chance for inclusion in the 2012 JAMA theme issue on cardiovascular disease. We encourage authors who anticipate presentation of late-breaking studies to communicate with editorial staff as early as possible.

IN 1900, HENRY FORD UNVEILED THE FIRST CAR MADE IN Detroit, the International Ladies’ Garment Workers Union was founded in New York, and San Francisco was placed under a federal quarantine to prevent the spread of bubonic plague. Infectious disease was a major concern, and the most common causes of death in the United States and in many parts of the world at the time were pneumonia and tuberculosis. Today, most individuals die of cardiovascular disease or cancer. This dramatic shift in the illnesses that cause the majority of death and disability has been divided into 4 stages known as the epidemiologic transition. In the last 2 decades, however, a fifth stage, marked by an alarming increase in overweight and obesity and continued decreases in physical activity, has emerged. This ongoing trend is addressed by 2 articles in this issue of JAMA. The first stage, which dominated most of human history, was characterized by pestilence and famine, when infectious diseaseandmalnutritionkeptaverage life expectancyat about 30 years. In the second stage, occurring in the late 19th and early 20th centuries in the United States and Europe, industrializationandurbanizationledto increasingwealthandacorresponding increase in the availability of food, an era termed receding pandemics. As the century continued, public health systems and cleaner water supplies and sewage systems combinedwithbetternutritiondrovedowndeaths frominfectious diseaseandmalnutrition, leading todeclining infantandchild mortalityandan increased lifeexpectancy.The thirdstage,degenerativeandhuman-madediseases,characterizedbyincreasingmortality fromcardiovasculardiseaseandcancer, emerged in the mid 20th century. Smoking, decreased activity levels in theworkplaceandathome,andincreasedintakeofanimalproductsandfatsresultedinincreasingprevalenceofelevatedblood pressure and cholesterol levels. Age-adjusted cardiovascular disease and cancer rates were at their peak. By the mid 1960s, the United States had entered the fourth stage of delayed degenerative diseases. Cardiovascular disease mortality declined, related to preventive strategies such as smoking cessation programs and effective blood pressure control, acute coronary care units, and technological advances that included coronary artery bypass surgery. Despite the many advances in preventive medicine and treatment that reduced cardiovascular disease, the new stage of the epidemiologic transition, the age of obesity and inactivity, emerged to threaten the progress made in postponing illness and death to later in adult life spans. The steady gains made in both quality of life and longevity by addressing risk factors such as smoking, hypertension, and dyslipidemia are threatened by the obesity epidemic. Over the last 40 years, the proportion of the US population considered to be overweight (body mass index [BMI] 25.0) and obese (BMI 30.0) has steadily increased. In the 1960-1962 National Health Examination Survey, an estimated 31.6% of men and women met the definition for “preobesity” (BMI between 25.0 and 29.9), and 13.4% were obese. The latest prevalence and trends in obesity data from the National Health and Nutrition Examination Survey (NHANES), reported by Flegal and colleagues in this issue of JAMA, show that in 2007-2008, 68.0% of US adults were overweight, of whom 33.8% were obese. More men than women were overweight or obese, 72.3% compared with 64.1%. If the increase inobesitywere tocontinueonthesametrack, researchers recently predicted that by 2020 almost half of US adults would meet the World Health Organization criteria for obesity. Compared with the previous 10-year period, the latestNHANESdatasuggest that thesteadyupwardtrendinoverweight and obesity may have slowed. Even though this finding is certainly good news, the statistics are still staggering— mostAmericansareoverweightandathirdareobese—asobering situation, given the wide variety of deleterious health effects strongly linked to excess weight. These include increased risk of coronary heart disease, ischemic stroke, hypertension, dyslipidemia, type 2 diabetes, joint disease, cancer, sleep apnea, asthma, and a host of other chronic conditions. Analyses from a national survey of almost 10 000 US adults suggest that obesity is associated with more chronic disorders andpoorerhealth-relatedqualityof life thansmokingorproblem drinking. If left unchecked, overweight and obesity have the potential to rival smoking as a public health problem, potentially reversing the net benefit that declining smoking rates have had on the US population over the last 50 years. Excess weight carries not only an enormous personal burden but an economiconeaswell.Medicalspendingforobesity-relatedconditionsaccountedforanestimated10%oftotalannualUSmedi

Context Folate, vitamin B 6 , and vitamin B 12 are thought to play an important role in cancer prevention. Objective To evaluate the effect of combined folic acid, vitamin B 6 , and vitamin B 12 treatment on cancer risk in women at high risk for cardiovascular disease. Design, Setting, and Participants In the Women's Antioxidant and Folic Acid Cardiovascular Study, 5442 US female health professionals aged 42 years or older, with preexisting cardiovascular disease or 3 or more coronary risk factors, were randomly assigned to receive either a daily combination of folic acid, vitamin B 6 , and vitamin B 12 or a matching placebo. They were treated for 7.3 years from April 1998 through July 31, 2005. Intervention Daily supplementation of a combination of 2.5 mg of folic acid, 50 mg of vitamin B 6 , and 1 mg of vitamin B 12 (n = 2721) or placebo (n = 2721). Main Outcome Measures Confirmed newly diagnosed total invasive cancer or breast cancer. Results A total of 379 women developed invasive cancer (187 in the active treatment group and 192 in the placebo group). Compared with placebo, women receiving the active treatment had similar risk of developing total invasive cancer (101.1/10 000 person-years for the active treatment group vs 104.3/10 000 person-years for placebo group; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.79-1.18; P = .75), breast cancer (37.8/10 000 person-years vs 45.6/10 000 person-years, respectively; HR, 0.83; 95% CI, 0.60-1.14; P = .24), or any cancer death (24.6/10 000 person-years vs 30.1/10 000 person-years, respectively; HR, 0.82; 95% CI, 0.56-1.21; P = .32). Conclusion Combined folic acid, vitamin B 6 , and vitamin B 12 treatment had no significant effect on overall risk of total invasive cancer or breast cancer among women during the folic acid fortification era. Trial Registration clinicaltrials.gov Identifier: NCT00000541

ContextHigh plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown.ObjectiveTo determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease.Design, Setting, and ParticipantsDouble-blind randomized controlled trial (2001-2006) in 36 US Department of Veterans Affairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease (estimated creatinine clearance ≤30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (≥ 15 μmol/L).InterventionParticipants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo.Main Outcome MeasuresThe primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients.ResultsMean baseline homocysteine level was 24.0 μmol/L in the vitamin group and 24.2 μmol/L in the placebo group. It was lowered 6.3 μmol/L (25.8%; P

Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons.To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women.In the Women's Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years.Administration of 600 IU of natural-source vitamin E on alternate days.Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer.During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR, 1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53).The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.

Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer.To examine the effect of aspirin on the risk of cancer among healthy women.In the Women's Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39 876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years.A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942) administered every other day.Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points.No effect of aspirin was observed on total cancer (n = 2865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found.Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.

ContextAlthough it has been hypothesized that hypertension is in part an inflammatory disorder, clinical data linking inflammation with incident hypertension are scarce.ObjectiveTo examine whether C-reactive protein levels, a marker of systemic inflammation, are associated with incident hypertension.Design, Setting, and ParticipantsA prospective cohort study that began in 1992 of 20 525 female US health professionals aged 45 years or older who provided baseline blood samples with initially normal levels of blood pressure (BP) (systolic BP

ImportanceNumerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.ObjectiveTo determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.Design, Setting, and ParticipantsCase-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.ExposuresTwo APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.Main Outcomes and MeasuresThe primary outcome was AD case-control status, and secondary outcomes included age at AD onset.ResultsStage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10−6) and was associated with a reported younger age at AD onset (β, −5.87 years; 95% CI, −8.35 to −3.4 years; P = 3.4 × 10−6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, −5.23 years; 95% CI, −9.58 to −0.87 years; P = .02) and stage 3 (β, −10.15 years; 95% CI, −15.66 to −4.64 years; P = 4.0 × 10−4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.Conclusions and RelevanceIn this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.