Article | Open

Positive impact of the participation in the ENCHANTED trial in reducing Door-to-Needle Time

  • Scientific Reports 7, Article number: 14168 (2017)
  • doi:10.1038/s41598-017-14164-8
  • Download Citation
Published online:


Door-to-needle time (DNT) is a key performance indicator for efficient use of intravenous thrombolysis in acute ischemic stroke (AIS). We aimed to determine whether DNT improved over time in the Enhanced Control of Hypertension and Acute Stroke Study (ENCHANTED) and the clinical predictors of DNT. Temporal trends in DNT were assessed across fourths of time since activation of study centers using generalized linear model. Predictors of long DNT (>60 min) were determined in logistic regression models. Overall mean DNT (min) was 71.8 (95% confidence interval [CI] 70.4–73.2), but decreased significantly over time (fourths): 77.9 (74.9–80.9), 69.3 (66.7–72.0), 69.1 (66.5–71.8) and 71.4 (68.7–74.2) (P for trend, 0.003). The reduction in DNT was particularly marked in China (P for trend, 0.001), but was not significant across the other participating countries (P for trend, 0.065). Independent predictors of long DNT were recruitment from China, short onset-to-door time, lower numbers of patients treated per center, higher diastolic blood pressure, off-hour admission, and absence of proximal clot occlusion. DNT in ENCHANTED declined progressively during the trial, especially in China. However, DNT in China is still longer than the key performance parameter of ≤60 minutes recommended in guidelines. Effective national programs are needed to improve DNT in China.


Intravenous recombinant tissue plasminogen activator (rtPA) is the only approved medical reperfusion therapy for patients with acute ischemic stroke (AIS)1. Guidelines1,2 recommend this treatment to be initiated as soon as possible within 4.5 hours of stroke onset, as shorter onset-to-treatment time (OTT) translates into a better functional outcome3,4. OTT is composed of onset-to-door time (ODT) and door-to-needle time (DNT). However, it is difficult to accomplish improvement of ODT because campaigns aiming at raising public awareness of stroke symptoms have only limited impact on ODT5. Conversely, a focus on decreasing in-hospital DNT is feasible, valuable and arguably essential, for quality systems of stroke care1,6.

We used the dataset from the Enhanced Control of Hypertension and Acute Stroke Study (ENCHANTED)7,8 rtPA-dose comparison arm to determine (i) whether DNT improved over time among participants, (ii) the extent to which DNT in China differed from other regions, and (iii) the clinical predictors of DNT.


There were 3219 (97.3%) patients with available data were included in these analyses. Table 1 shows the baseline characteristics of patients by DNT (≤60 vs. >60 mins). The majority of participants (1903 [59.1%]) had DNT >60 m. These were significantly more likely to be younger, Chinese, hypertensive, off-hour admission, being treated in a larger center, and have longer ODT. Multivariable analysis shows the independent predictors of longer DNT included recruitment from China (OR 9.75, 95%CI 7.70–12.35; P < 0.0001), shorter ODT (0.58, 0.53–0.65; P < 0.0001), fewer patients treated in the center (0.96, 0.95–0.97; P < 0.0001), higher diastolic blood pressure (BP) (1.07, 1.00–1.14; P = 0.037), off-hour admission (1.27, 1.07–1.50; P = 0.005), and CT or MRI angiogram not showing proximal occlusion (0.65, 0.52–0.82; P = 0.0002). Chinese patients were twice as likely (1147, 83.0%) to have DNT >60 m compared to non-Chinese patients (756, 41.2%). Shorter ODT and fewer patients treated in the center were independently associated with DNT >60 m for both Chinese and non-Chinese patients. Among non-Chinese patients, male patients (female vs. male: 0.74 [0.61–0.90]; P = 0.003) and Asians (other than Chinese) (0.62, 0.51–0.76; P < 0.0001) were less likely to have DNT >60 m (see Supplementary Tables S1 and S2).

Table 1: Baseline characteristics of patients with acute ischemic stroke, according to door-to-needle time above and below 60 minutes for use of intravenous thrombolysis treatment.

Table 2 and Fig. 1 show that the overall mean DNT (min) was 71.8 (95%CI 70.4–73.2), and that it decreased significantly over the course of the trial (fourths): 77.9 (74.9–80.9), 69.3 (66.7–72.0), 69.1 (66.5–71.8) and 71.4 (68.7–74.2) (P for trend, 0.003) and this trend remained consistent after adjusting for confounders. In particular, there was a significant reduction of 33 minutes between the first and final fourth epocs in time across the trial in China (P for trend, 0.001), whilst there was little temporal difference in the other participating countries.

Table 2: Door-to-Needle time over time.
Figure 1
Figure 1

Correlation between time from the activation of each center in the ENCHANTED trial and door-to-needle time for (A) all patients, (B) Chinese patients, and (C) non-Chinese patients.


These analyses of a large clinical trial dataset involving AIS patients treated in a wide range of hospitals in multiple countries shows that DNT, whilst longer than recommended in best practice guidelines, progressively decreased in centers over the course of the study. In particular, centers in China achieved a 33 minutes reduction in DNT over three years of participation in ENCHANTED, whilst DNT remained consistent elsewhere. Aside from recruitment in China, the independent predictors of long DNT included shorter ODT, fewer patients treated at a center, higher diastolic BP, off-hour admission, and the absence of proximal occlusion on imaging.

Our analysis demonstrated that there has been a significant reduction in DNT over time for patients in China, which was not matched by reductions in other regions. However, there is still a large gap between the DNT in China (mean DNT 97.5 min, which is consistent with some previous observational studies in China) and the quality performance DNT of <60 min recommended in international guidelines8,9,10,11. Although various quality improvement efforts have been undertaken in China in the last decade, resulting in dramatic improvements in acute stroke care, there remains significant gaps between guideline recommendations and clinical practice in this country9. The Target Stroke Initiative, launched by the American Heart Association and American Stroke Association in 2011, was successful at improving the timeliness of rtPA administration for AIS on a national scale in the United States10,12,13. A similar comprehensive program is clearly needed in China, with ongoing monitoring of DNT as an important benchmark for quality in stroke care1,10,11,12. Why DNT did not improve for non-China centers (mean 57.1 min) may relate to the already strong performance and low volumes compared with Chinese centers.

Our analyses identified some interesting factors influencing DNT. Firstly, our data confirm the paradox that shorter ODT is associated with longer DNT13,14,15. This suggests that the responsible medical officer may be influenced by the perception that there is ample time prior to the expiration of the thrombolysis window - this may be especially true in China12,16. Secondly, in line with previous reports14,17, we found that hospitals with higher annual volumes of thrombolysis activity achieved significantly shorter DNT. This may relate to high-volume hospitals having better processes in place for investigation and decision-making for rtPA administration17. Thirdly, our analysis of higher diastolic BP being associated with longer DNT supports the findings of Skolarus et al. who reported that pre-thrombolytic antihypertensive treatment for patients with elevated BP prolongs DNT in a secondary analysis of a clinical trial population18. Furthermore, our analysis demonstrates that off-hour admission was an independent predictor of longer DNT, which may be due to reduced hospital staffing and delayed imaging procedures during off-hour time19,20.

Key strengths of our study include the large sample size of patients, and the rigorous evaluation7,8. However, as ENCHANTED excluded those patients who were likely to die within the next 24 hours, the present findings may not be generalizable to patients with severe AIS. In addition, several factors which influence DNT, including hospital pre-notification by ambulances10 and time needed for informed consent and randomization, were not collected and thus excluded from the adjusted analyses.

In summary, DNT progressively declined among centers participating in the ENCHANTED trial, especially in China. However, as DNT remains longer than the 60 minute cut-point recommended in guidelines, national programs to improve the timeliness of delivery of rtPA are needed in China.



The ENCHANTED trial is an international, multi-center, prospective, randomized, open-label, blinded-endpoint trial; the details of which are outlined elsewhere7,8,21. In brief, 3310 patients with a clinical diagnosis of AIS confirmed on brain imaging and fulfilling local criteria for thrombolysis treatment, including symptom onset within 4.5 hours, participated in the rtPA dose evaluation arm, where they were randomly assigned to receive low- (0.6 mg/kg; 15% as bolus, 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as   bolus, 90% as infusion over 1 hour) rtPA. The study protocol was approved by Ethics Committee of Peking University First Hospital and appropriate ethics committee at each participating center. Written informed consent was obtained from each patient or their appropriate surrogate. Participants of this study were managed according to standard guidelines and protocols at each hospital.


Key demographic and clinical characteristics were recorded at the time of enrolment, with stroke severity measured using the National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) at baseline, 24 hours, and at Day 7 (or earlier on discharge from hospital). Uncompressed digital images of all baseline and follow-up digital CT, MRI and angiogram images were collected in DICOM format on a CD-ROM identified only with the patient’s unique study number, and uploaded by a special purpose-built web-based system for central analysis at The George Institute of Global Health.

Statistical Analysis

Independent predictors of long DNT (>60 min) were determined using logistic regression models. Significant predictors (P < 0.05) from the univariate analysis were tested for their association with long DNT (>60 min) in a multivariable model. We reduced the full model by successively removing nonsignificant covariates until all the remaining predictors remained statistically significant (P < 0.05). Correlation between time from the activation of each center and DNT was assessed using Spearman Correlation. DNT was log-transformed to remove skewness. Generalized linear model was used to investigate secular trends in DNT across fourths of time since the start of each site with adjustment for all independent predictor of long DNT.

Data availability

The dataset analysed in the current study are available upon appropriate request sent to a corresponding author.

Additional Information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Jauch, E. C. et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44, 870–947 (2013).

  2. 2.

    Demaerschalk, B. M. et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 47, 581–641 (2016).

  3. 3.

    Lees, K. R. et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375, 1695–1703 (2010).

  4. 4.

    Saver, J. L. et al. The “golden hour” and acute brain ischemia: presenting features and lytic therapy in >30,000 patients arriving within 60 minutes of stroke onset. Stroke 41, 1431–1439 (2010).

  5. 5.

    Kruyt, N. D. et al. Door-to-needle time and the proportion of patients receiving intravenous thrombolysis in acute ischemic stroke: uniform interpretation and reporting. Stroke 44, 3249–3253 (2013).

  6. 6.

    Fonarow, G. C. et al. Improving door-to-needle times in acute ischemic stroke: the design and rationale for the American Heart Association / American Stroke Association’s target: Stroke Initiative. Stroke 42, 2983–2989 (2011).

  7. 7.

    Anderson, C. S. et al. Statistical analysis plan for evaluating low- vs. Standard-dose alteplase in the enhanced control of hypertension and thrombolysis stroke study (enchanted). Int J Stroke 10, 1313–1315 (2015).

  8. 8.

    Anderson, C. S. et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. New Engl J Med 374, 2313–2323 (2016).

  9. 9.

    Wang, Y. et al. Stroke care quality in China: substantial improvement, and a huge challenge and opportunity. Int J Stroke 12, 229–235 (2017).

  10. 10.

    Fonarow, G. C. et al. Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. J Am Med Assoc 11, 1632–1640 (2014).

  11. 11.

    Ruff, I. M. et al. Improving door-to-needle times: a single center validation of the target stroke hypothesis. Stroke 45, 504–508 (2014).

  12. 12.

    Huang, Q. et al. Generalization of the right acute stroke prevention strategies in reducing in-hospital delays. PloS One. 11, e0154972 (2016).

  13. 13.

    Mikulik, R. et al. Factors influencing in-hospital delay in treatment with intravenous thrombolysis. Stroke 43, 1578–1583 (2012).

  14. 14.

    Strbian, D. et al. Relationship between onset-to-door time and door-to-thrombolysis time: a pooled analysis of 10 dedicated stroke centers. Stroke 44, 2808–2813 (2013).

  15. 15.

    Ferrari, J. et al. Stroke thrombolysis: having more time translates into delayed therapy: data from the Austrian stroke unit registry. Stroke 41, 2001–2004 (2010).

  16. 16.

    Huang, Q. et al. Factors associated with in-hospital delay in intravenous thrombolysis for acute ischemic stroke: lessons from China. PloS One. 10, e0143145 (2015).

  17. 17.

    Bray, B. D. et al. Bigger, faster? Associations between hospital thrombolysis volume and speed of thrombolysis administration in acute ischemic stroke. Stroke 44, 3129–3135 (2013).

  18. 18.

    Skolarus, L. E. et al. Antihypertensive treatment prolongs tissue plasminogen activator door-to-treatment time: secondary analysis of the INSTINCT trial. Stroke 43, 3392–3394 (2012).

  19. 19.

    Hasegawa, Y. et al. The effect of weekends and holidays on stroke outcome in acute stroke units. Cerebrovasc Dis 20, 325–331 (2005).

  20. 20.

    Saposnik, G. B. A., Bayer, N. & Hachinski, V. Weekends: a dangerous time for having a stroke? Stroke 38, 1211–1215 (2007).

  21. 21.

    Huang, Y. et al. Rationale, design, and progress of the enhanced control of hypertension and thrombolysis stroke study (ENCHANTED) trial: an international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. Guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment. Int J Stroke 10, 778–788 (2015).

Download references


The work was supported by grant (APP1020462) from the National Health and Medical Research Council of Australia, grant (TSA 2012/01) from the Stroke Association of United Kingdom, and grant from National Natural Science Foundation of China (81471199) and Department of Science and Technology of Jiangsu Province (BK20161113). The study was designed, conducted, analyzed and interpreted by the investigators independent of sponsors. We thank the efforts of ENCHANTED Investigators for conduct the trial and data collection.

Author information


  1. Department of Neurology, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China

    • Jie Yang
    •  & Jian ping Yu
  2. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia

    • Jie Yang
    • , Xia Wang
    • , Richard I. Lindley
    •  & John Chalmers
  3. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    • Jing Hang
  4. Servicio de Neurología, Departamento de Medicina, ClínicaAlemana, Universidad del Desarrollo, and Universidad de Chile, Santiago, Chile

    • Pablo Lavados
  5. Department of Cardiovascular Sciences and NIHR Biomedical Research Centre, University of Leicester, Leicester, UK

    • Thompson Robinson
  6. Department of Public Health, Fukuoka University, Fukuoka, Japan

    • Hisatomi Arima
  7. The George Institute for Global Health at Peking University Health Science Center, Beijing, China

    • Craig S. Anderson


  1. Search for Jie Yang in:

  2. Search for Xia Wang in:

  3. Search for Jian ping Yu in:

  4. Search for Jing Hang in:

  5. Search for Pablo Lavados in:

  6. Search for Thompson Robinson in:

  7. Search for Hisatomi Arima in:

  8. Search for Richard I. Lindley in:

  9. Search for Craig S. Anderson in:

  10. Search for John Chalmers in:


J.Y., J.H., J.C., R.L. and C.S.A. wrote the main manuscript text. J.Y. and C.S.A. contributed equally the idea and funding. X.W. and H.A. performed the statistical analysis. J.P.Y. prepared figures and tables. T.R. contributed funding and comments. All authors reviewed the manuscript.

Competing Interests

P.M. Lavados reports receiving research funding from Astra Zeneca, Bayer and Boehringer Ingelheim and speaking fees from Bayer. T. Robinson is a National Institute of Health Research Senior Investigator, and reports receiving speaking fees from Bayer and Boehringer Ingelheim, and fees for Advisory Panels from Bayer and Daiichi Sankyo. R.I. Lindley reports receiving speaking fees from Boehringer Ingelheim, Covidien, and Pfizer. C.S. Anderson reports receiving fees for Advisory Panels of Astra Zeneca and Medtronic, speaking at seminars for Takeda China and Boehringer Ingelheim. J. Chalmers reports research grants and lecture fees from Servier for the ADVANCE trial and post-trial follow-up. Jie Yang, Xia Wang, Jian ping Yu, Jing Hang, and Hisatomi Arima declare no potential conflict of interest.

Corresponding authors

Correspondence to Jie Yang or Craig S. Anderson.

Electronic supplementary material


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Creative Commons BY

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit