Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.

To the Editor: Lopez et al. report that ‘‘cholinesterase inhibitor (CEI) use had a clinically meaningful effect on the natural history of Alzheimer Disease (AD),’’ slowing disease progression and lowering risk of nursing home admission after 2 years. The design of the study is worrisome. Of 1,139 patients who enrolled in the AD Research Center over 7 years, 270 were selected; 135 began taking CEIs ‘‘immediately after enrollment, and continued to take them throughout the following 12 months,’’ and 135 never took the drug. How these individuals were selected is not otherwise described. They were matched on a few characteristics, such as age, Mini-Mental State Examination score, and education. This study resembles a study by Dr. Geldmacher et al. that showed that patients who took a CEI faithfully (80% of pills or more) had a significant delay in nursing home placement (NHP). Both of these nonrandomized studies failed to report important baseline characteristics of the groups being studied. In the Geldmacher article, for example, nonadherent patients were far less likely to have a spouse caregiver than faithful users, yet the authors, who claimed it was the donepezil that ‘‘resulted in significant delays in NHP,’’ omitted this fact. Both papers are easily distinguished from AD 2000, a properly randomized, controlled trial with the largest number of placebo-controlled patient-years of any cholinesterase study. In AD 2000, ‘‘no significant benefits were seen with donepezil compared with placebo in institutionalization or progression of disability . . . [or] in behavioral and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events, or death or between 5 mg and 10 mg of donepezil.’’ In the United Kingdom, the National Institute for Clinical Excellence Appraisal Committee has recently issued the following preliminary recommendation: ‘‘Donepezil, rivastigmine and galantamine are not recommended for use in the treatment of mild to moderate Alzheimer’s disease (AD).’’ Would Dr. Lopez modify the discussion of his paper, where he emphasizes the important benefits of donepezil, in view of the results from AD 2000, a larger, better-designed trial that failed to show any meaningful difference at all?

OBJECTIVES: To determine the influence of advanced age on anticoagulant use in subjects with atrial fibrillation and to explore the extent to which risk factors for stroke and contraindications to anticoagulant therapy predict subsequent use.DESIGN: Retrospective cohort study.SETTING: The Veterans Affairs Boston Healthcare System.PARTICIPANTS: A total of 2,217 subjects with nonvalvular atrial fibrillation.MEASUREMENTS: Administrative databases were use to identify subject's age, anticoagulant use, and the presence of a diagnosis of atrial fibrillation, cerebrovascular accident, hypertension, diabetes mellitus, congestive heart failure, or gastrointestinal or cerebral hemorrhage.RESULTS: Unadjusted analysis showed no difference in warfarin use between those aged 75 and older and younger subjects regardless of the presence (33.9% vs 35.7%, P=.37) or absence (33.4% vs 34.7%, P=.58) of contraindications to anticoagulant therapy. Multivariate modeling demonstrated a 14% reduction (95% confidence interval (CI)=4-22%) in anticoagulant use with each advancing decade of life. Intracranial hemorrhage was a significant deterrent (odds ratio (OR)=0.27 95% CI=0.06-0.85). History of hypertension (OR=2.90, 95% CI=2.15-3.89), congestive heart failure (OR=1.70, 95% CI=1.41-2.04), and cerebrovascular accident (OR=1.54, 95% CI=1.25-1.89) were significant independent predictors for anticoagulant use.CONCLUSION: Despite consensus guidelines to treat all atrial fibrillation patients aged 75 and older with anticoagulants, advancing age was found to be a deterrent to warfarin use. Better estimates of the risk:benefit ratio for oral anticoagulant therapy in older patients with atrial fibrillation are needed to optimize decision-making.

Background-Both aspirin and warfarin when used alone are effective in the secondary prevention of vascular events and death after acute myocardial infarction. We tested the hypothesis that aspirin and warfarin therapy, when combined, would be more effective than aspirin monotherapy.Methods and Results-We conducted a randomized open-label study to compare the efficacy of warfarin (target international normalized ratio 1.5 to 2.5 IU) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5059 patients enrolled within 14 days of infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank P=0.76). Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank P=0.52). Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively; P<0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups.Conclusions-In post-myocardial infarction patients, warfarin therapy (at a mean international normalized ratio of 1.8) combined with low-dose aspirin did not provide a clinical benefit beyond that achievable with aspirin monotherapy.

Rapid reduction of excessively high international normalized ratio (INR) values into the therapeutic range is necessary in patients who must be maintained on oral anticoagulants but who present with an overdose. We prospectively studied the effect of observation alone versus escalating low doses of intravenous vitamin K on 23 patients presenting with no overt evidence of hemorrhage and INR values in excess of 10. Two of six patients observed without intervention developed spontaneous hemorrhage. Only one of the observed patients and none of 4 patients given 100-200 µg-vitamin K had INR values less than 5.0 by 24 hours. Three of the four patients receiving 500 µg of vitamin K had INR values less than 5.0, with two of these being less than 3.5 within the first 24 hours. Nine patients receiving 1000 µg of vitamin K had INR values between 1.7 and 3.5 by 24 hours. In none of these nine patients did the INR subsequently normalize, and there were no difficulties re-establishing anticoagulant therapy. No adverse effects were noted in any of the patients receiving intravenous vitamin K. We recommend 1000 µg of intravenous vitamin K as a safe and effective means of rapidly reversing excessively anticoagulated patients presenting with INR values greater than 10 units.

We performed a metaanalysis of five randomized controlled trials to compare the efficacy and safety of combined oral anticoagulant and antiplatelet therapy versus oral anticoagulants alone after prosthetic heart-valve replacement. The combined regimen reduced embolism and overall mortality by approximately 67% (pooled odds ratio [OR] 0.33; 95% confidence interval [CI] 0.16 to 0.69; p = 0.0032) and 40% (OR 0.60; 95% CI 0.32 to 1.12; p = 0.11), respectively, but increased the risk of hemorrhage by approximately 65% (OR 1.65; 95% CI 1.15 to 2.39; p = 0.0069) and of major gastrointestinal hemorrhage by approximately 250% (OR 3.47; 95% CI 1.43 to 8.40; p = 0.0058). It is estimated that for every 1.6 patients who had their stroke prevented by combination therapy, there was an excess of one major gastrointestinal bleed. This metaanalysis suggests that the benefits derived from the enhanced antithrombotic potential of combined therapy outweigh the toxic effects resulting from the enhanced anticoagulant potential of this regimen.

The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.

The ability of the prothrombin time to measure the anticoagulant effect of warfarin sodium varies depending on the particular tissue thromboplastin used in performing the test. Based on studies using sensitive thromboplastins, lower therapeutic ranges of anticoagulation are recommended. The adequacy of monitoring therapy in this lower range with the relatively insensitive thromboplastins commonly used in North America is unestablished. This 16-month prospective study used a standard North American thromboplastin to monitor 157 anticoagulated patients treated in a low therapeutic range. Of the 1734 prothrombin times generated, 876 (56%) were therapeutic, with 400 (23%) below and 458 (26%) above the therapeutic range. These results are comparable with those published in trials in which more sensitive thromboplastins were used in a similar therapeutic range. We conclude that standard North American thromboplastins are adequately suited to monitor therapy in this lower range.

The authors measured the template bleeding time in 11 normal people before and 2, 4, 12, 24, and 48 hours after the subjects ingested a single dose of 74 mg of aspirin (ASA). The entire experiment was repeated twice at two-week intervals, with the dose of ASA increased to 325 mg and finally 3,900 mg. The mean increase was maximal at 4 and 12 hours, regardless of the dose administered, with a return to baseline by 48 hours. The authors then performed bleeding times in a prospective randomized double-blinded fashion on an additional 39 subjects at baseline and seven hours after they ingested either placebo or ASA 325 mg. The mean baseline bleeding time was 5.2 minutes (SD +/- 1.4), with a mean prolongation after ASA of 2.1 minutes (SD +/- 1.9). The authors identified 5 of 37 (14%) subjects as hyper-responders (HRs) using the criterion of a bleeding time prolongation of greater than 5.9 minutes (greater than 2 SD beyond the mean prolongation). Neither baseline bleeding time, threshold sensitivity of collagen-induced platelet aggregation, nor other tests of hemostatic function discriminated HRs from normals. The authors conclude that in subjects with normal baseline bleeding times, a prolongation of greater than 5.9 minutes when measured seven hours after the administration of a single dose of 325 mg of ASA can discriminate HRs from normals.