July 2014 FAQs

Can patients with recurrent C difficile infection be treated with a prepared fecal microbiota transplant product?

Introduction

Recently, the use of fecal microbiota transplant (FMT) for recurrent Clostridium difficile infection (RCDI) has garnered attention because of new clinical and regulatory developments.1-4 Clinical data for FMT have been promising, although concerns regarding the origin, preparation, and distribution of FMT have led to complicated regulatory considerations. As a result, some clinicians are uncertain how FMT is regulated and how candidate patients can obtain FMT therapy, specifically at institutions unable to prepare FMT locally.

Rationale, efficacy, and safety of FMT

Fecal microbiota transplant consists of the transplantation of donor stool into the gastrointestinal tract of a patient with RCDI via colonoscopy, enema, or nasogastric tube.1-4 Patients with RCDI have often been treated with multiple courses of antibiotics, which may negatively alter the composition of gut microbiota and promote susceptibility to recurrent or worsening infection. Alterations in the gut microbiota compromise the normal beneficial functions of bacteria, such as synthesis of vitamins, metabolism of bile, and resistance to colonization by exogenous pathogenic bacteria. Transplantation of donor stool is believed to reestablish the quantity and quality of the colonic microbiome, providing resolution of RCDI via restoration of normal microbial diversity.

Recently, the first randomized controlled trial (RCT) of FMT in patients with RCDI supported its efficacy and safety.5 van Nood and colleagues randomized 42 patients to nasoduodenal FMT following a 4-day vancomycin regimen and bowel lavage, a standard 14-day vancomycin regimen, or a standard vancomycin regimen without bowel lavage. Patients assigned to FMT achieved a significantly greater clinical resolution rate compared with the standard vancomycin regimens (81% vs 31% and 23%, respectively; p<0.01 for both comparisons). The trial was halted early due to the highly significant and favorable effect of FMT. A second RCT compared colonoscopic with nasogastric administration of frozen FMT products in patients with RCDI.6 Among 10 patients randomized to each arm, the primary endpoint of clinical resolution occurred in 80% and 60% of patients who received colonoscopic and nasogastric administration, respectively (p=0.628); these numbers increased to 100% and 80% after retreatment (p=0.53). No adverse events directly attributable to FMT were reported.

Previously, numerous retrospective studies were performed and were evaluated in a meta-analysis.7 Kassam and colleagues analyzed 11 studies of 273 RCDI patients treated with FMT, finding a clinical resolution rate of 89% (95% confidence interval [CI]; 84% to 93%) when FMT was delivered by any modality (colonoscopy, enema, gastroscopy, or nasojejunal or nasogastric tube). Subgroup analyses suggested a trend toward improved outcomes with delivery of FMT at lower (colonoscopy and enema) versus upper (nasogastric/nasojejunal tube and gastroscopy) gastrointestinal sites (proportion difference, 10.6%; 95% CI, -0.6% to 21.8%). No significant differences in outcomes were identified when stool originated from patient-selected versus anonymous donors (proportion difference -0.7%; 95% CI, -10.5% to 9.1%).

The risk of infection with FMT is a clear concern necessitating further long-term study, although safety is supported by the current evidence base. 5,7 No significant differences in adverse events occurred between patients in the single RCT except for belching, mild diarrhea, and abdominal cramping, which were seen predominantly on the day of FMT rather than during follow-up.5 In numerous retrospective studies with follow-up ranging from several weeks to years, no serious adverse events were reported that could be directly attributable to FMT.7 Studies to date have minimized infection risk by screening both blood and stool, commonly testing for hepatitis A, B, and C; Campylobacter; C difficile; Shigella; Salmonella; Treponema pallidum; Yersinia; ova; and parasites.

These favorable data have led to a growing acceptance of FMT as a legitimate therapy for RCDI. For example, a survey of gastrointestinal and infectious disease physician specialists found over 80% would refer patients for FMT.8 Furthermore, numerous practitioners have registered with the American Gastroenterological Association as FMT practitioners.9 While no guidelines on FMT are available from professional societies, a working guideline from the Fecal Microbiota Transplant workgroup is available and has been recognized in the medical literature.3,10 Despite this, regulatory issues may complicate the use of FMT in practice.

Regulation of FMT as an investigational drug

In May of 2013, a workshop was held between members of the scientific and healthcare communities and the US Food and Drug Administration (FDA). 11 Prior to this, clinicians utilizing FMT were required to submit an investigational new drug (IND) application for FMT because the treatment met the definition of a biologic.12 However, some providers felt this requirement would hinder the availability of FMT for patients in urgent need, and, therefore, suggested a different regulatory approach was warranted. In July 2013, the FDA issued guidance on their intended enforcement policy, stating they would “exercise enforcement discretion” regarding the requirement of an IND application for FMT in patients with RCDI not responsive to standard therapies.11 The statement suggested that an IND application is not required, but encouraged in such cases, and that informed consent of the risks and investigational nature of FMT was explicitly required.1,11 However, FMT for other indications would continue to require an IND application.3,11 This guidance was immediately implemented; a public comment period was determined to be detrimental because of its required duration, which may have prohibited the timely availability of FMT to patients with severe infection in urgent need of FMT.11

Further clarification came in a new draft of the enforcement policy in March 2014, which proved controversial due to the renewed potential for barriers in utilizing FMT.13 The FDA clarified when it would exercise enforcement discretion, indicating this would occur when patients provide informed consent, the stool donor and stool are both qualified by screening and testing by the healthcare provider, and the FMT product is obtained from a donor “known to either the patient or the treating licensed health care provider.” Most contentious of these is the final criterion. “Known donors” may be difficult to identify or excluded based on screening criteria, and stool procurement from such donors may limit the timeliness of therapy in severe cases. Likewise, the current draft fails to define in detail what constitutes a “known” donor. Thus, FMT from a “universal donor” may be warranted.14 This alternative has been invoked to oppose any potential intervention by FDA when universal donor stool is used; it has been cited by the Infectious Disease Society of America, the Society for Healthcare Epidemiology of America, and the Fecal Transplant Foundation as rationale to remove this provision from the current draft guidance.14-16 Importantly, the draft guidance requiring that stool for FMT originate from a known donor is open for public comment, and the July 2013 enforcement policy is still the current acting guidance. Therefore, universal donor stool can currently be used without IND requirements during the process of consideration for the proposed draft.17

Options for procuring FMT

The first FDA enforcement policy provided new opportunity to care for patients with otherwise limited treatment options for RCDI, though obtaining and processing donor stool still proved challenging.1 For example, individual institutions that prepared FMT locally would be required to process stool via detailed procedures and with specific equipment, which may not be feasible in all settings.18,19

Commercially available FMT product can be procured via OpenBiome, the first national stool bank, which has provided treatment to over 400 patients. 20,21 OpenBiome acquires donor stool from a population of healthy young individuals who pass screening, testing, and ongoing monitoring criteria for general health and common and serious infectious pathogens.22 The organization offers products in 250-mL colonoscopic and 30-mL nasogastric formats, which normally cost a total of $500 for product and overnight shipping. The organization provides further information online on issues related to procurement, processing, regulation, and insurance.23

Summary

Fecal microbiota transplant is an alternative therapy for RCDI with an evidence base and regulatory framework that continue to develop. Further well-designed trials and long-term safety evaluations are necessary, although current data generally support the practice. This has led to a growing acceptance of FMT and the establishment of a stool bank that provides FMT products. However, the current draft FDA enforcement policy may in the future require filing of an IND application for patients receiving FMT provided by universal donors. Until regulation is fully clarified, clinicians using FMT to treat patients with RCDI should adhere to the acting enforcement policy, ensuring that patients provide informed consent and that donor and stool are adequately screened and tested, regardless of whether the source is from a known or universal donor.

References

1. Moore T, Rodriguez A, Bakken JS. Fecal microbiota transplantation: a practical update for the infectious disease specialist. Clin Infect Dis. 2014;58(4):541-545.

2. Gens KD, Elshaboury RH, Holt JS. Fecal microbiota transplantation and emerging treatments for Clostridium difficile infection. J Pharm Pract. 2013;26(5):498-505.

3. Austin M, Mellow M, Tierney WM. Fecal Microbiota Transplantation in the Treatment of Clostridium difficile Infections. Am J Med. 2014;127(6):479-483.

4. Lo Vecchio A, Cohen MB. Fecal microbiota transplantation for Clostridium difficile infection: benefits and barriers. Curr Opin Gastroenterol. 2014;30(1):47-53.

5. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.

6. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58(11):1515-1522.

7. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508.

8. Jiang ZD, Hoang LN, Lasco TM, Garey KW, Dupont HL. Physician attitudes toward the use of fecal transplantation for recurrent Clostridium difficile infection in a metropolitan area. Clin Infect Dis. 2013;56(7):1059-1060.

9. Fecal microbiotia transplantation: Find a practitioner. American Gastroenterological Association website. http://fmt.gastro.org/find-a-practitioner/. Accessed June 9, 2014.

10. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9(12):1044-1049.

11. US Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry: enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. US Food and Drug Administration website. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM361393.pdf. Accessed June 9, 2014.

12. What are "biologics" questions and answers. US Food and Drug Administration website. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm133077.htm. Updated April 14, 2009. Accessed June 20, 2014.

13. US Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry: Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. US Food and Drug Administration website. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM387255.pdf. Accessed June 10, 2014.

14. Infectious Diseases Society of America. Fecal microbiota transplantation. Infectious Diseases Society of America website. www.idsociety.org/FMT/. Accessed June 9, 2014.

15. Comment from Society for Healthcare Epidemiology of America. Regulations.gov website. http://www.regulations.gov/#!documentDetail;D=FDA-2013-D-0811-0015. Updated May 13, 2014. Accessed June 9, 2014.

16. Comment from The Fecal Transplant Foundation. Regulations.gov website. http://www.regulations.gov/#!documentDetail;D=FDA-2013-D-0811-0005. Updated March 26, 2014. Accessed June 9, 2014.

17. What is the regulatory environment for FMT? OpenBiome website. http://www.openbiome.org/regulatory-support/. Accessed June 9, 2014.

18. Fecal microbiota transplant (FMT) protocol by enema for patients with recurrent Clostridium difficile infection. Infectious Diseases Society of America website. http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/Emerging_Clinical_Issues/FMT/FMT%20by%20enema%20Moore(1).pdf. Accessed June 10, 2014.

19. Fecal microbiota transplant (FMT) treatment protocol by nasoduodenal tube for patients who experience recurrent episodes of Clostridium difficile infection (RCDI). Infectious Diseases Society of America website. http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/Emerging_Clinical_Issues/FMT/FMT%20by%20Nasoduodenal%20tube%20JSB.pdf. Accessed June 10, 2014.

20. @OpenBiome. Great day presenting OpenBiome at #asm2014! Also thrilled to share that we've passed the 400 treatment mark! https://twitter.com/OpenBiome/status/468777841694629888. Posted May 20, 2014.

21. About OpenBiome. OpenBiome website. http://www.openbiome.org/about-us/. Accessed June 10, 2014.

22. Safety and quality assurance. OpenBiome website. http://www.openbiome.org/safety-quality-assurance/. Accessed June 10, 2014.

23. How to work with OpenBiome. OpenBiome website. http://www.openbiome.org/how-to-work-with-openbiome/. Accessed June 10, 2014.

July 2014

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What data are available comparing liposomal bupivacaine to other agents?

Introduction

Local anesthetics, non-steroidal anti-inflammatory drugs (NSAIDs) and/or opioids may be used as part of a multidrug regimen to provide adequate analgesia after surgical procedures.1,2 The selection of a particular local anesthetic is based on the onset and duration of the anesthetic, its adverse effects, the type of procedure, and level of anticipated pain.3 Of the currently available local anesthetics, ropivacaine and bupivacaine are long-acting agents that are used for local infiltration. A liposomal formulation of bupivacaine hydrochloride approved for local infiltration of the surgical site for postsurgical anesthesia may theoretically prolong the duration of action of bupivacaine. The slow release of bupivacaine from the liposome has been shown to maintain systemic plasma concentrations over 96 hours.4 This formulation is intended to provide analgesia through the postoperative period to reduce the need for opioids and, thereby, minimize opioid-related adverse effects. This review will summarize the current data on the comparative efficacy, safety, and affordability of liposomal bupivacaine.

Literature review

The Table below summarizes the currently published comparative trials of liposomal bupivacaine. All trials compare the liposomal formulation to either bupivacaine hydrochloride or opioid patient-controlled analgesia (PCA)except for the retrospective cohort study by Bagsby5, which compares efficacy to ropivacaine. The findings of this study demonstrated that pain scores were not significantly different between the 2 groups in the first 24 hours and were lower in the ropivacaine group 24 hours after surgery until discharge.5

Compared to bupivacaine hydrochloride, liposomal bupivacaine did not consistently demonstrate significantly improved pain scores.5-11 In most trials, opioid consumption was found to be significantly less with liposomal bupivacaine; however, opioid-related adverse events were not significantly different between groups in all trials. Hospitalization costs were found to be less in patients who received liposomal bupivacaine in 2 of the 3 trials that evaluated this outcome; however, all 3 trials had a sample size less than 50 patients.6-8

Table. Comparative liposomal bupivacaine studies.5-11

In a 2012 analysis of published studies and abstracts, Dasta and colleagues compared the pooled efficacy and safety of liposomal bupivacaine to bupivacaine hydrochloride.12 Included studies were double-blind, active or placebo-controlled trials using a single dose of ≤266 mg liposomal bupivacaine injected into the surgical site before the end of surgery. Outcome measures included the 72-hour cumulative pain score as measured by the 11-point numeric rating scale (NRS), time to first use of opioid rescue medication, total opioid consumption (expressed as morphine equivalents) in 72 hours, overall adverse events, and opioid-related adverse events (pruritus, respiratory depression, vomiting, and urinary retention). Results of 9 studies were evaluated with 505 patients in the liposomal bupivacaine group and 406 in the bupivacaine hydrochloride group. Surgical procedures included inguinal hernia repair, knee arthroplasty, hemorrhoidectomy, breast augmentation, and bunionectomy. The mean area under the curve (AUC) of NRS scores through 72 hours was significantly lower with liposomal bupivacaine compared to bupivacaine hydrochloride (283 vs. 329, respectively, p=0.039). Median time to opioid administration was significantly longer with liposomal bupivacaine compared to bupivacaine hydrochloride (2.7 h vs. 9.9 h, respectively, p<0.0001). Patients receiving liposomal bupivacaine consumed a lower average amount of opioids (12.2 mg) compared to patients in the bupivacaine hydrochloride group (19 mg, p<0.0001). Common adverse events observed in both groups included nausea, constipation, vomiting, pyrexia, pruritus, and dizziness. Significantly more patients reported opioid-related adverse effects in the bupivacaine hydrochloride group (36%) compared to patients in the liposomal bupivacaine group (20%, p<0.0001). The authors concluded that liposomal bupivacaine can provide longer analgesia with less opioid consumption compared to bupivacaine hydrochloride. Of note, this analysis included 2 placebo-controlled studies and results of another pooled analysis. It is unknown whether exclusion of these studies would affect the results of this analysis.

Conclusion

The comparative data currently available for liposomal bupivacaine are limited to comparisons to either bupivacaine hydrochloride or opioid PCA. The most commonly used liposomal bupivacaine dose used was 266 mg. The only other comparison was to ropivacaine in a retrospective cohort study. When compared to bupivacaine hydrochloride, pain scores were lower or similar with liposomal bupivacaine. This may partly be due to the higher opioid consumption in the bupivacaine hydrochloride group. The outcome that consistently demonstrated a potential advantage is total opioid consumption. However, the incidence of opioid-related adverse events was not significantly different between groups in the individual studies and was only found to be significant in the pooled analysis. The small sample size of these studies precludes making firm conclusions on the advantages of liposomal bupivacaine over bupivacaine hydrochloride. Larger, prospective, randomized trials comparing liposomal bupivacaine to bupivacaine hydrochloride and other analgesic regimens can help further define its role in postsurgical analgesia and whether its use translates to a reduction in opioid-related adverse effects, shorter length of stay, and reduced hospitalization costs.

References

1. Slevin KA, Ballantyne JC. Slevin K.A., Ballantyne J.C. Management of acute postoperative pain. In: Longnecker DE, Brown DL, Newman MF, Zapol WM. Longnecker D.E., Brown D.L., Newman M.F., Zapol W.M. eds. Anesthesiology. 2nd ed. New York, NY: McGraw-Hill; 2012. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=490&Sectionid=4011476. Accessed May 20, 2014.

2. Simopoulos TT. Preemptive analgesia. In: Warfield CA, Bajwa ZH. Warfield C.A., Bajwa Z.H. eds. Principles and Practice of Pain Medicine. 2nd ed. New York, NY: McGraw-Hill; 2004. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=411&Sectionid=4042983. Accessed May 20, 2014.

3. Tsai T, Gadsden J, Connery C. Tsai T, Gadsden J, Connery CLocal infiltration anesthesia. In: Hadzic A. Hadzic A ed. NYSORA Textbook of Regional Anesthesia and Acute Pain Management. New York, NY: McGraw-Hill; 2007. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=413&Sectionid=3982815. Accessed May 20, 2014.

4. Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals; 2011.

5. Bagsby DT,Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty . 2014 Apr 4. doi: 10.1016/j.arth.2014.03.034.

6. Vogel JD. Liposome bupivacaine (EXPAREL®) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial. J Pain Res. 2013;6:605-610.

7. Marcet JE, Nfonsam VN, Larach S. An extended pain relief trial utilizing the infiltration of a long-acting multivesicular liposome formulation of bupivacaine, EXPAREL (IMPROVE): a Phase IV health economic trial in adult patients undergoing ileostomy reversal. J Pain Res. 2013;6:549-555.

8. Cohen SM. Extended pain relief trial utilizing infiltration of Exparel(®), a long-acting multivesicular liposome formulation of bupivacaine: a Phase IV health economictrial in adult patients undergoing open colectomy. J Pain Res. 2012;5:567-572.

9. Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg. 2012;78(5):574-581.

10. Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19(5):530-536.

11. Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, active-control study. Aesthet Surg J. 2012;32(1):69-76.

12. Dasta J,Ramamoorthy S,Patou G, Sinatra R. Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting. Curr Med Res Opin . 2012;28(10):1609-1615.

July 2014

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What is the Target: Stroke initiative and its effect on stroke outcomes?

Introduction

Stroke is the most common disabling neurologic disorder.1 Ischemic stroke, specifically, refers to the abrupt onset of a “focal neurologic deficit” resulting from ischemia. The pathophysiology, though complex, involves occlusion of a blood vessel that leads to interruption of blood flow, thereby interfering with neurologic function dependent upon the affected region. Primary treatment of acute ischemic stroke requires thrombolysis to dissolve the active embolism, as well as potential mechanical clot-retrieval in order to reduce disability and mortality. With approximately 750,000 new strokes and 150,000 deaths from stroke occurring each year in the United States, it remains a large health burden.1,2 Of special concern is the fact that incidence of stroke increases with age, with approximately two-thirds of all strokes occurring in adults aged 65 years and above.1

Due in part to increasing efforts by the American Heart Association/American Stroke Association (AHA/ASA) to reduce stroke, coronary heart disease, and cardiovascular risk, stroke has dropped from third to fourth-leading cause of death in the United States.2 Because of the importance of rapid treatment with recombinant tissue plasminogen activator (rtPA), national guidelines currently advise intravenous (IV) administration of the medication within 3 to 4.5 hours of initial symptoms, and initiation within 60 minutes of arrival to the hospital in eligible patients.2,3 Prior studies, however, demonstrated that less than one-third of patients in the United States that present to hospitals with ischemic stroke achieved this optimal door-to-needle time (DTN).4,5 Fonarow et al demonstrated that 18,714 of 25,504 (73.4%) patients had DTN times longer than 60 minutes, with a median time to administration of 78 minutes.4 The authors also found that in-hospital mortality was lower for patients with DTN times less than 60 minutes (adjusted odds ratio [OR], 0.78; 95% confidence interval [CI], 0.69 to 0.90; p<0.0003). Albers et al found a median emergency department arrival to rtPA treatment time of 96 minutes, with a 30-day mortality rate of 13% (n=382 patients).5

In 2004, the AHA/ASA launched the Get With the Guidelines (GWTG)-Stroke program, with the aim of reducing disparities among hospitals with regards to acute stroke care through workshops, clinical decision tools, and reporting via the Internet-based Patient Management Tool.6 With the frequency of IV rtPA use almost doubling from 2003 to 2011, the need to administer it appropriately, rapidly, and optimally is greater than ever.7 As such, in 2010, the AHA/ASA launched another national quality improvement initiative entitled Target: Stroke.3

Target: Stroke Initiative

A major component of Target: Stroke is to achieve reduction in DTN times and increase the portion of eligible acute ischemic stroke patients who receive rtPA ≤60 minutes after hospital arrival.3 The primary goal of the initiative is to have administration of rtPA to at least 50% of patients within 60 minutes of hospital arrival.3,8 Especially important to the Target: Stroke initiative are the feasibility and cost-effectiveness of implementation.

The strategies to achieve this were assembled by an expert group performing systematic reviews of all published data on improving DTN times, which identified 10 evidence-based strategies associated with time stroke reperfusion.8 Some of the strategies included promotion of pre-notification of hospitals by emergency medical services personnel, a team-based approach, activation of a stroke team by a single call or page, use of stroke protocols, premixing of rtPA, and rapid feedback of team performance.3,8

Early validation of the Target: Stroke initiative at a single center (based on an analysis of 2595 patients) showed significant improvement in both door-to-computed tomography times <25 minutes (26.7% pre-intervention vs 52.3% post-intervention; p <0.001) and DTN times <60 minutes (32.4% pre-intervention vs 70.3% post-intervention; p <0.001) in patients presenting to the hospital with a last-known-well time within 180 minutes. 9 These promising results lend credence to the Target: Stroke initiative. However, improvement to time of care has not always translated into improved outcomes. A recent 2013 analysis by Menees et al showed that despite the improvement of national door-to-balloon times in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention, in-hospital mortality remained unchanged, bringing to question the true benefit of more rapid medical interventions in general.11 Though evaluating a different acute condition, the Menees et al study looked at the similar outcomes, namely ischemic time and short-term mortality rates. Thus, a study to reinforce the clinical benefit of the Target: Stroke initiative was conducted.

Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative

In April 2014, Fonarow et al published a study evaluating the principle results from the initiative, in which they analyzed temporal trends in DTN times as well as the proportion of patients within a DTN time of 60 minutes or less before and after initiation of Target: Stroke.3 In addition, the authors set out to validate whether shorter DTN times were indeed linked to improved clinical outcomes. The 10 key strategies described above were provided to all GWTG-Stroke participant hospitals, along with tools such as protocols, order sets, algorithms, time trackers, and patient education materials, all provided through the Target: Stroke website (www.targetstroke.org).8 These hospitals were also encouraged to share best practices and provide feedback, all believed to be essential to the eventual successful implementation of the initiative.

The study was comprised of 71,169 acute ischemic stroke (AIS) patients (27,319 during the pre-intervention period from April 2003 to December 2009, and 43,850 during the post-intervention period from January 2010 to September 2013) from 1,030 GWTG-Stroke participating hospitals.3 Baseline characteristics were similar between pre- and post-intervention periods, with a median patient age of 72 years and nearly equal numbers of men and women. A majority of patients were excluded due to treatment >3 hours after stroke onset or receiving treatment at a hospital not participating in the study during both the pre- and post-intervention periods. Measured outcomes included in-hospital all-cause mortality, disposition upon discharge (e.g., home vs. long-term care facility), ability to ambulate, symptomatic intracranial hemorrhage (ICH) after receiving rtPA, and overall complications from rtPA administration.

The authors found a median DTN time during the pre-intervention period of 77 minutes, which decreased to 67 minutes in the post-intervention period (p<0.001).3 The number of patients achieving a DTN time ≤60 minutes increased from a pre-intervention percentage of 26.5% to a post-intervention percentage of 41.3% (p<0.001). Further, they determined that the median onset-to-treatment time decreased from 137 minutes in the pre-intervention period to 128 minutes during the post-intervention period (p<0.001). Of note, the use of rtPA in AIS patients actually increased in the post-intervention period (8.1%) from the pre-intervention period (5.7%) (p<0.001). With regards to clinical outcomes, the post-intervention period was associated with significantly reduced in-hospital mortality (8.25% vs 9.93%, p<0.001), increased discharge to home (42.7% vs 37.6% to acute rehabilitation, skilled nursing facility, etc; p<0.001), more frequent independent ambulation by the AIS patient (45.4% vs 42.2%, p<0.001), lower incidence of symptomatic ICH (4.68% vs 5.68%, p<0.001), and less complications from rtPA (5.50% vs 6.68%, p<0.001). Notably, once an adjusted OR was calculated, ambulatory status of patients between pre- and post-intervention was no longer significant (adjusted OR 1.03, 95% CI 0.97 to 1.10) (p = 0.31). However, other outcomes (mortality, discharge to home, symptomatic ICH, and rtPA complications) remained significant (p<0.001) in favor of shorter DTN times.

Fonarow et al concluded that the Target: Stroke initiative was associated with significant improvement in the timely administration of rtPA.3 The authors linked the quality improvement with decreases in in-hospital mortality, symptomatic ICH, and overall rtPA complications, as well as an increase in the number of patients able to go home and ambulate independently. Despite the demonstrated clinical benefits from this study, concerns in relation to more rapid DTN times for rtPA administration have arisen due to the potential for rushed neurological assessments, inappropriate patient selection, and increased administration errors. Fonarow et al, however, concluded that their findings show that the benefits outweigh the risks and are enough to justify implementation of the Target: Stroke initiative nationwide to help improve outcomes following an AIS.

The primary strength of the study includes its sheer size, both in terms of sample and scale, making it more generalizable to the population at large. 3 It was the first study of its kind to implement a full set of tools to help hospitals improve their DTN times. The study is not without its limitations, however. First, the study relied upon retrospective data. Also, because participation was voluntary, participating hospitals were likely to have greater interest and willingness to adopt the changes. Further, hospitals may have increased rtPA usage since they knowingly and voluntarily were participating in this intervention, potentially inflating results inappropriately. Another issue was the lack of a control group. A third limitation was the lack of accounting for confounders; it is quite possible that clinical outcomes improved due to factors aside from DTN time. Additionally, the pre-intervention period was far longer than that of the post-intervention period, making comparability more difficult to achieve.

Conclusions

Current guidelines advise a rapid DTN time of <60 minutes once the patient arrives at the hospital.2,3 With data prior to this study suggesting that reduced DTN times lead to reduced disability and mortality, the need had arisen for interventions that would facilitate more rapid administration of rtPA after initial symptoms, prompting the implementation of Target: Stroke.1,3,8 With the Target: Stroke initiative coming into fruition and being implemented in over 1,000 hospitals across the nation, DTN times were significantly reduced.3.9 The Fonarow et al study displayed the potential clinical benefits of reducing DTN times, as it was associated with decreased mortality and overall rtPA complications (including symptomatic ICH), and an increase in patients able to go home and ambulate independently.3

Although the data are still relatively new, all signs point toward the benefits of the Target: Stroke initiative. The initiative is fairly straightforward and includes the 10 evidence-based strategies (e.g., promotion of pre-notification of hospitals by EMS personnel, a multidisciplinary approach, use of protocols and tools, and premixing of rtPA) that are already present in some form at most participating hospitals, and if not, are easily attained through the Target: Stroke website.3,8 Due to its feasibility, cost-effectiveness, and ease of implementation, this quality improvement initiative should continue to be implemented at medical centers around the United States. Clinicians, however, should be vigilant when it comes to administration of rtPA, as the potential risks of inappropriate patient selection and dosing errors may increase as hospitals attempt to meet these recommended DTN times. One must never rush the assessment if it means compromising quality and safety of a patient’s care. Further studies and assessment of these strategies are needed to truly elucidate the clinical value and safety of reduced DTN times.

References

1. Greenberg DA, Aminoff MJ, Simon RP, eds. Clinical Neurology. 8th ed. New York, NY: McGraw-Hill; 2012. http://accessmedicine.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=398&Sectionid=39812250. Accessed May 09, 2014.

2. Jauch EC, Saver JL, Adams HP Jr, et al. American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. 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. 2013;44(3):870-947.

3. Fonarow GC, Zhao X, Smith EE, 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. JAMA. 2014;311(16):1632-1640.

4. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation. 2011;123(7):750-758.

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8. Fonarow GC, Smith EE, Saver JL, 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. 2011;42(10):2983-2989.

9. Ruff IM, Ali SF, Goldstein JN, et al. Improving door-to-needle times: a single center validation of the target stroke hypothesis. Stroke. 2014;45(2):504-508.

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11. Menees DS, Peterson ED, Wang Y, et al. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013;369(10):901-909.

Prepared by:

Gabriel Gonzaga, PharmD

PGY-1

University of Illinois at Chicago

July 2014

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