JACC VOL. 67, NO. 5, 2016


FEBRUARY 9, 2016:596–602

REPLY: Survival Differences in Clinical Trials


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


(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






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


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,


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



JACC VOL. 67, NO. 5, 2016


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-






dividual (including miRNAs), they may come close to


being accurate for that person. However, as far as I


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












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.


If medicine ever becomes “precise and accurate,”







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



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.

Precision Medicine, Obstructive Sleep Apnea, and Refractory Hypertension.

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