JACC VOL. 67, NO. 5, 2016
Letters
FEBRUARY 9, 2016:596–602
REPLY: Survival Differences in Clinical Trials
REFERENCE
With Long-Term Follow-up
1. Henderson RA, Jarvis C, Clayton T, Pocock SJ, Fox KAA. 10-Year mor-
We thank Dr. Kostis and colleagues for their comments on our recent paper (1) reporting the 10-year
tality outcome of a routine invasive strategy versus a selective invasive strategy in non-ST-segment elevation acute coronary syndrome: the British Heart Foundation RITA-3 randomized trial. J Am Coll Cardiol 2015;66: 511–20.
mortality outcomes of the RITA-3 trial. We agree that relative differences in mortality between randomized groups may attenuate over time as more deaths occur in each group, and estimation of average survival may provide an alternative approach to evaluating the effects of treatment. Restricted
Precision Medicine, Obstructive Sleep Apnea, and Refractory Hypertension
mean survival analysis (to estimate the area between the survival curves out to 10 years) gave a mean sur-
In 2015, authors are beginning to use the term pre-
vival difference of 0.18 years in favor of a routine
cision medicine as if whatever it is they are testing
invasive strategy with a 95% confidence interval
will result in a favorable response to therapy based
of 0.44 to 0.08 years, p ¼ 0.170. These results are
on a single diagnostic test. In this instance, Sanchez-
compatible with the survival differences reported in
de-la-Torre et al. (1) measured plasma micro ribonu-
our paper and support our conclusion that the reduced
cleic acids (miRNAs) and reported that this substance
mortality associated with the routine invasive strat-
will predict blood pressure responses to continuous
egy at 5 years attenuates during later follow-up.
positive airway pressure treatments in patients with
Moreover, RITA-3 recruited patients with non–
refractory hypertension and obstructive sleep apnea
syndrome
(OSA). My interpretation of this article is that miR-
before the widespread use of drug-eluting stents and
NAs will predict that response in many but not all
other novel therapies. The impact of contemporary
patients with OSA and refractory hypertension. Thus,
invasive strategies on longer term mortality is there-
this measurement can have statistical significance for
fore unknown, supporting our call for further ran-
a favorable response in populations, but the indi-
domized trials. In the interim, guideline committees
vidual patient may or may not respond in a similar
will need to consider our results, and any long-term
fashion.
ST-segment
elevation
acute
coronary
results of the FRISC-2 (Fragmin and Fast Revascu-
The word precision can be defined simply as
larisation during Instability in Coronary artery dis-
reproducibility and does not necessarily mean that
ease 2) and ICTUS (Invasive versus Conservative
the diagnosis or outcome is accurate. Accuracy is
Treatment in Unstable Coronary Syndromes) trials,
defined as being near to the true or desired value.
when determining whether their recommendations
Consider a target on a rifle range; if the shots have a
need to be revised.
tight grouping anywhere on the target, they are precise, but they are only precise and accurate if that
*Robert A. Henderson, DM Chris Jarvis, MSc Tim Clayton, MSc Stuart J. Pocock, PhD Keith A.A. Fox, MB, ChB
individual patient based on multiple pieces of infor-
*Trent Cardiac Centre
required. miRNAs can be part of those multiple pieces
Nottingham University Hospitals
of information that influence judgment, similar to
City Hospital Campus
other pieces of clinical information. These other
Hucknall Road
pieces of clinical information can include risk profiles
Nottingham, Nottinghamshire
such as Framingham risk assessment, clinical trials
NG96BG
data, family history, chronic kidney disease, obesity,
United Kingdom
diabetes, as well as imaging studies, blood tests,
E-mail:
[email protected] functional studies, genetics, and common sense,
http://dx.doi.org/10.1016/j.jacc.2015.10.087
often related to experience. However, despite this
Please note: RITA-3 was funded by a competitive grant from the British Heart Foundation, and the British Heart Foundation received a donation from Aventis Pharma. Additional governmental support (Culyer) was obtained to reimburse interventional centers for part of the costs of percutaneous coronary intervention procedures on trial patients. Mr. Clayton has received grant support from The Medicines Company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
reasonable approach, even genetic profiles do not
tight grouping is in the bull’s-eye. Most clinicians must make clinical decisions for an mation. To make the right clinical decision for the right patient at the right time, judgment is
guarantee that the genotype will become the phenotype in an individual patient. I believe that an individual’s genetic data are powerful factors (and miRNAs may be as well), but they do not always result
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JACC VOL. 67, NO. 5, 2016
Letters
FEBRUARY 9, 2016:596–602
in the expected clinical outcome, just like other
medicine is defined as “treatments targeted to
clinical factors.
the needs of individual patients on the basis of
When all of these factors are evaluated for the in-
genetic,
biomarker,
phenotypic,
or
psychosocial
dividual (including miRNAs), they may come close to
characteristics
being accurate for that person. However, as far as I
from
can tell, prognostication of outcome is easily deter-
sentations” (2). The HIPARCO score (1,3), based
mined for populations, but prognostication of an
on epigenetics analysis, is able to distinguish “a given
other
that
distinguish
patients
with
a
given
similar
patient
clinical
pre-
individual’s response to therapy is an educated guess.
patient from other patients with similar clinical pre-
I am all for being as precise and accurate as
sentations.” The results of our study show that if a
possible when making decisions about individual
patient obtains a HIPARCO score of 0 or 6, the prob-
patients. Unfortunately, so far, clinical decisions are
ability of making the appropriate clinical decision is
not as precise and accurate as one would like.
higher
If medicine ever becomes “precise and accurate,”
than
94%.
This
instrument
could
help
physicians make precise and accurate decisions.
there will be no need for judgment by physicians. In
Medicine was originally an art, and the generation
fact, there may not be any need for physicians. In my
of knowledge over time made it a science. Medical
opinion, clinical judgment is still necessary to make
practice must become as precise and accurate as
clinical decisions in the individual patient, and it will
possible, and it is the primary role of research to lead
stay that way for a long time.
the way toward this milestone.
*Richard Conti, MD *Cardiology
Manuel Sánchez-de-la-Torre, PhD *Ferran Barbé, MD
University of Florida
*Respiratory Department, IRB Lleida. CIBERES
1600 SW Archer Road
Hospital Universitari Arnau de Vilanova Rovira Roure, 80
Gainesville, Florida 32610
25198 Lleida
E-mail:
[email protected]fl.edu
Spain
http://dx.doi.org/10.1016/j.jacc.2015.09.111
E-mail:
[email protected] Please note: Dr. Conti has reported that he has no relationships relevant to the contents of this paper to disclose.
http://dx.doi.org/10.1016/j.jacc.2015.10.088 Please note: Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCE 1. Sánchez-de-la-Torre M, Khalyfa A, Sánchez-de-la-Torre A, et al. Precision medicine in patients with resistant hypertension and obstructive sleep apnea: blood pressure response to continuous positive airway pressure treatment. J Am Coll Cardiol 2015;66:1023–32.
REPLY: Precision Medicine, Obstructive Sleep Apnea, and Refractory Hypertension We appreciate Dr. Conti’s comments regarding our study (1) and share his thoughts. However, precision
REFERENCES 1. Sánchez-de-la-Torre M, Khalyfa A, Sánchez-de-la-Torre A, et al. Precision medicine in patients with resistant hypertension and obstructive sleep apnea. J Am Coll Cardiol 2015;66:1023–32. 2. Jameson JL, Longo DL. Precision medicine–personalized, problematic, and promising. N Engl J Med 2015;372:2229–34. 3. Martínez-García MA, Capote F, Campos-Rodriguez F, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013;310: 2407–15.