Incomplete Revascularization

JACC VOL. 69, NO. 1, 2017

Letters

JANUARY 3/10, 2017:107–18

substituting platelet function testing. We agree that

would include the differential impact of IPC on the

the identification of factors associated with impaired

effect of various P2Y12 inhibitors, the mechanisms

response to antiplatelet therapy is of major impor-

leading to this effect, and the association with clinical

tance because understanding the mechanisms might

outcome.

help improve future therapies. Even if the present

currently known predictor of antiplatelet response to

*Christian Wilhelm Stratz, MD Franz-Josef Neumann, MD Willibald Hochholzer, MD

thienopyridines, it could only predict <20% of vari-

*University Heart Center Freiburg $ Bad Krozingen

ability in antiplatelet response. Thus, predictors of

Department of Cardiology and Angiology II

platelet response currently cannot substitute platelet

Suedring 15

function testing as correctly concluded by Bonello

79189 Bad Krozingen

and colleagues and already previously demonstrated

Germany

study was able show that the immature platelet count (IPC) is an independent and probably the strongest

for genetic factors (2). We agree that strong evidence supports direct testing of on-treatment platelet reactivity as predictor of clinical outcome. However, it is still uncertain if current platelet function tests can provide

E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2016.09.976 Please note: Dr. Stratz has received lecture fees from Eli Lilly. Dr. Hochholzer has received lecture fees from Daiichi Sankyo, Bristol-Myers Squibb, and Boehringer Ingelheim. Dr. Neumann has reported that he has no relationships relevant to the contents of this paper to disclose.

optimal risk prediction because their readouts vary significantly over time (3,4). Moreover, no large

REFERENCES

randomized trial could demonstrate a clinical benefit

1. Stratz C, Bomicke T, Younas I, et al. Comparison of immature platelet count to established predictors of platelet reactivity during thienopyridine therapy. J Am Coll Cardiol 2016;68:286–93.

of platelet function testing in guiding antiplatelet therapy. Presently, it might be a potential limitation that IPC is not available in all settings. However, various manufacturers offer hematology equipment that can assess parameters of immature platelets. Usually, it

2. Hochholzer W, Trenk D, Fromm MF, et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010;55:2427–34.

only requires a software upgrade to run immature

3. Hochholzer W, Ruff CT, Mesa RA, et al. Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the

platelet parameters as a simple and cheap routine

ELEVATE-TIMI 56 trial. J Am Coll Cardiol 2014;64:361–8.

laboratory parameter.

4. Nuhrenberg TG, Stratz C, Leggewie S, et al. Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation. An ADAPT-DES substudy. Thromb Haemost 2015;114: 1020–7.

We do not agree that immature platelets reflect only thrombopoiesis and platelet turnover, which should explain the effect of immature platelets on short-lived actives metabolites such as clopidogrel. As recently demonstrated, platelet turnover is not the

5. Stratz C, Nuehrenberg T, Amann M, et al. Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover. Thromb Haemost 2016;116:941–8.

major factor causing these effects pointing toward certain intrinsic properties of these cells (5). In this study, the correlation of IPC with impaired antiplatelet response to thienopyridines was similar in the very early phase and late after thienopyridine

Incomplete Revascularization

loading indicating a mechanism independent from

The Achilles Heel of Percutaneous

platelet turnover. As potential alternative mecha-

Coronary Interventions

nism, a stronger cellular response to external stimulation (e.g., with adenosine diphosphate) could be demonstrated for reticulated platelets as compared to

We read with great interest the study of Chang

nonreticulated platelets.

et al. (1), reporting that in patients with 3-vessel

Thus, immature platelets represent a very inter-

coronary artery disease (90% of the patients in the

esting subfraction of platelets and IPC appears to be

study) and complex coronary anatomy, as defined

the most robust parameter. We agree, however, that

by intermediate or high SYNTAX score, coronary

immature platelets are more a piece of the puzzle

artery

than the missing link when deciphering the entire

reduced all-cause 5-year mortality and myocardial

story of platelet response to antiplatelet therapy. We

infarction as compared to percutaneous coronary

need further data before we can recommend assess-

intervention. These findings are consistent with

ment of IPC in clinical routine. As mentioned, this

previous reports and with the current recommended

bypass

graft

surgery

is

associated

with

115

116

JACC VOL. 69, NO. 1, 2017

Letters

JANUARY 3/10, 2017:107–18

guidelines for the management of patients with

University of California, San Diego

multivessel disease.

9434 Medical Center Drive

A very interesting question that could have been

San Diego, California 92037

addressed by the authors given their access to patient

E-mail: [email protected]

level data was whether similar benefits are observed

http://dx.doi.org/10.1016/j.jacc.2016.07.790

after complete revascularization (CR). Although not studied in a prospective randomized study, CR has been shown in multiple, large retrospective studies to be associated with lower short- and long-term mortality, lower rate of myocardial infarction, and repeat revascularization independent of the initial revascularization strategy (2,3). In both the SYNTAX and BEST trials, CR was significantly lower in the percutaneous coronary intervention groups (4,5): 56.7% versus 63.2% (p ¼ 0.005) in the SYNTAX (The Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial and 50.9% versus 71.5% (p < 0.001) in the BEST (The Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) trial. Less frequent CR could in part explain the difference in outcomes and thus raises a very important question, does surgery offer additional clinical benefits independent of CR? CR has for long been the goal of surgical revascu-

Please note: Dr. Patel has served on the Speakers Bureau for AstraZeneca and the Medicines Company; and has served as a consultant for AstraZeneca, the Medicines Company, Abbott Vascular, and Avinger. Dr. Mahmud has served on the Speakers Bureau for Medtronic and Abbott Vascular; has been on the advisory board for Medtronic; has served as a Consultant for Abbott Vascular; and has served on the Clinical Events Committee for FAME 2 and FAME 3 clinical studies. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

REFERENCES 1. Chang M, Ahn JM, Lee CW, et al. Long-term mortality after coronary revascularization in nondiabetic patients with multivessel disease. J Am Coll Cardiol 2016;68:29–36. 2. Farooq V, Serruys PW, Garcia-Garcia HM, et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol 2013;61:282–94. 3. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol 2013;62:1421–31. 4. Serruys P, Garg S. Percutaneous coronary interventions for all patients with complex coronary artery disease: triple vessel disease or left main coronary artery disease. Yes? No? Don’t know? Rev Esp Cardiol 2009;62:719–25. 5. Park SJ, Ahn JM, Kim YH, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med 2015;372:1204–12.

larization, yet among interventional cardiologists the adoption of this concept has been more gradual. However, with increasing success rates in chronic total occlusion revascularization and the use of fractional flow reserve, the field of interventional cardiology is much more capable of achieving functional CR. Fractional flow reserve–based revascularization reduces major adverse cardiac events in patients with

Long-Term Mortality After Coronary Revascularization in Nondiabetic Patients With Multivessel Disease

multivessel disease, comparable to those reported with surgery in the SYNTAX and BEST trials, suggesting that complete functional revascularization

Recently the Journal published a pooled data of 2

may be comparable to coronary artery bypass graft

randomized clinical trials (RCT) comparing coronary

surgery. The eagerly awaited FAME-3 (Fractional

artery bypass grafting (CABG) versus drug-eluting

Flow Reserve versus Angiography for Multivessel

stents (DES) in patients without diabetes with

Evaluation 3) study should shed more light on this

multiple-vessel disease (1).

very important clinical question. Until that time,

CABG was associated with significantly lower

incomplete revascularization is looked on as an

incidence of death (p ¼ 0.037), myocardial infarction

Achilles heel; a very important and relevant clinical

(MI) (p < 0.001), and adverse cardiac events across all

variable that remains to be accounted for and could

groups including DES designs and there was no trial

potentially be addressed by Chang et al. (1).

interaction for the primary outcome (p ¼ 0.913).

Ali Pourdjabbar, MD Benjamin Hibbert, MD, PhD Mitul P. Patel, MD Ryan R. Reeves, MD *Ehtisham Mahmud, MD

data of RCT with bare-metal stents versus CABG (2),

In contrast, if we remembered previous pooled

*Division of Cardiovascular Medicine Sulpizio Cardiovascular Center

we realized that they did not find differences either in death (p ¼ 0.78) or in death and MI (p ¼ 0.64) without interaction between patients with diabetes and those without (p ¼ 0.65). What was done in percutaneous coronary intervention (PCI) between both analyses (1,2)?