N-of-1 or single subject clinical trials consider an individual patient as the sole unit of observation in a study investigating the efficacy or side-effect profiles of different interventions. The ultimate goal of an n-of-1 trial is to determine the optimal or best intervention for an individual patient using objective data-driven criteria. Such trials can leverage study design and statistical techniques associated with standard population-based clinical trials, including randomization, washout and crossover periods, as well as placebo controls. Despite their obvious appeal and wide use in educational settings, n-of-1 trials have been used sparingly in medical and general clinical settings. We briefly review the history, motivation and design of n-of-1 trials and emphasize the great utility of modern wireless medical monitoring devices in their execution. We ultimately argue that n-of-1 trials demand serious attention among the health research and clinical care communities given the contemporary focus on individualized medicine.
We thank Dr Nezami and colleagues for their interest in our study. As they note, statin therapy has been associated with improved clinical outcomes after percutaneous coronary intervention. Although an early observational study suggested an interaction between atorvastatin and the antiplatelet effect of clopidogrel in the acute phase of treatment, presumably due to shared metabolism via the CYP3A4 pathway, this does not occur during maintenance clopidogrel therapy and was not confirmed in subsequent randomized pharmacodynamic studies. In addition, clinical outcome studies have failed to identify a clear impact of statins on the ability of clopidogrel to reduce recurrent ischemic events. 1 In order to address the questions of Dr Nezami and colleagues about our trial, we assessed the effect of statin use in GRAVITAS by incorporating this covariate into our time-dependent multivariate regression model. 2 Statin use was not associated with clinical outcome at 60 days (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI], 0.27-3.02) or 6 months (adjusted HR 0.86. 95% CI, 0.39 -1.91), nor did it affect the relationship between on-treatment reactivity Ͻ208 PRU and outcome at either time point (adjusted HR 0.23, 95% CI, 0.05-0.98, Pϭ0.047 at 60 days and adjusted HR 0.54, 95% CI: 0.28 -1.04, Pϭ0.064 at 6 months). Admittedly, the power to detect differences in outcomes according to statin use was severely limited because periprocedural myocardial infarction was not a component of the primary end point and 88% of the enrolled patients were taking a statin at discharge. We unfortunately did not systematically collect the types of statin used, and therefore we cannot address potential differences between lipophilic and hydrophilic statins. However, posthoc analyses of several large randomized clinical trials, including Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22), found no impact of adding atorvastatin to patients already on clopidogrel. 3 Dr De Miguel Castro and colleagues posit that a threshold value for on-treatment reactivity may depend on clinical presentation. Yet in GRAVITAS we found that the threshold of on-treatment reactivity Ն208 PRU was independently associated with clinical events even after adjustment for acute coronary syndrome. 2 In the recently reported Assessment of Dual AntiPlatelet Therapy with DrugEluting Stents (ADAPT-DES) study, which involved Ͼ8000 patients treated with percutaneous coronary intervention, on-treatment reactivity Ͼ208 PRU was associated with a Ͼ5-fold risk of definite stent thrombosis after adjustment for acute coronary syndrome presentation. 4 Similarly, in a pooled patient-level meta-analysis of observational studies, there was no interaction between clinical presentation with or without acute coronary syndrome and the risk of death, myocardial infarction, or stent thrombosis in patients with high on-treatment reactivity. 5 Differences in analytic approaches, combined with differences in population ch...
BACKGROUND A new miniature high-resolution pocket-mobile echocardiographic (PME) device has become available to clinicians, but there are no data available comparing this technology with standard transthoracic echo (TTE) examination. OBJECTIVE To assess the potential validity of PME imaging as a quick assessment of cardiovascular disease by direct comparison to standard TTE. DESIGN Ultrasonographers attempted to acquire seven standard echocardiography views with the PME prior to performing comprehensive standard TTEs. In blinded fashion, images from the two modalities were compared by two experienced echocardiographers and two cardiology fellows. PRIMARY FUNDING SOURCE This work was funded in part by Scripps Health and the NIH UL1 RR025774 (Scripps Translational Science Institute, Clinical and Translational Science Award). SETTING Scripps Clinic/Green Hospital PATIENTS 97 consecutive unselected patients MEASUREMENTS Comparisons were made in regards to ejection fraction (EF), segmental wall motion abnormalities (WMA), left ventricular end-diastolic dimension (LVEDD), inferior vena cava (IVC) size, aortic and mitral valve pathology, and pericardial effusion. RESULTS PME images were adequate for interpretation of EF in 95% of the studies, LVEDD 95%, mitral valve 90%, WMA 83%, aortic valve 83%, and IVC 75%. Compared to standard TTE, PME interpretation by attendings and fellows had an accuracy of 97% and 93% for EF, respectively. Likewise, accuracy for WMA was 90% and 87% ; LVEDD 94% and 91%; aortic stenosis 97% and 95%; mitral abnormality 88% and 82%; and IVC size 81% and 74%. LIMITATIONS As this was a validation study of imaging alone, further evaluation with clinician image acquisition is needed. CONCLUSIONS PME images obtained rapidly by skilled ultrasonographers provide excellent visualization in the vast majority of patients and correlate well with standard, comprehensive TTE. Such validation needs to be extended to untrained clinicians in larger and diverse patient populations before broad dissemination of this technology can be recommended.
Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)(n). We asked whether variation at (TCAT)(n) may influence the autonomic nervous system and its response to environmental stress. To understand the role of heredity in such traits, we turned to a human twin study design. Both biochemical and physiological autonomic traits displayed substantial heritability (h(2)), up to h(2) = 56.8 +/- 7.5% (P < 0.0001) for norepinephrine secretion, and h(2) = 61 +/- 6% (P < 0.001) for heart rate. Common (TCAT)(n) alleles, particularly (TCAT)(6) and (TCAT)(10i), predicted such traits (including catecholamine secretion, as well as basal and poststress heart rate) in allele copy number dose-dependent fashion, although in directionally opposite ways, indicating functional allelic heterogeneity. (TCAT)(n) diploid genotypes (e.g., [TCAT](6)/[TCAT](10i)) predicted the same physiological traits but with increased explanatory power for trait variation (in contrast to allele copy number). Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)(10i) allele on both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)(6) allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, "intermediate phenotypes" in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the tyrosine hydroxylase locus exerts a powerful, heritable effect on autonomic control of the circulation and that such variation may have implications in later development of cardiovascular disease traits such as hypertension.
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