A. Trials of clopidogrel in combination with aspirin after stroke/TIA suggest that the combination reduces risk of stroke but increases risk of major hemorrhage. However, the risk of thrombosis is extremely high in the acute period after TIA and minor stroke. The risk of hemorrhage is expected to be lower after TIA compared to a completed stroke, and is much lower for minor ischemic stroke compared to the strokes of moderate severity enrolled in MATCH. Thus, the combination of clopidogrel-aspirin may be particularly effective and relatively safe in patients with TIA and minor ischemic stroke.
The majority of patients (79%) enrolled in the MATCH trial suffered a prior stroke, rather than TIA. In a subgroup analysis, there was a trend toward greater benefit in those treated sooner after the qualifying stroke or TIA, with a 17% relative risk reduction in those treated within 7 days.
In a meta-analysis of results from several trials for patients enrolled within 24 hours of onset of TIA or stroke, there was a relative risk reduction of 34% with clopidogrel-aspirin vs. aspirin alone for the composite outcome measure of stroke, TIA, acute coronary syndrome, and all-cause death, providing further evidence that the impact of clopidogrel-aspirin may be substantial in the acute period.
The combination clopidogrel-aspirin may be particularly effective early after acute ischemia, when the risk of recurrent ischemia is particularly high and platelet aggregation likely to be highly relevant.
2.Q. Why are the results from the CHANCE trial, showing clopidogrel plus aspirin to be more effective than aspirin alone for POINT-like patients, not generalizable to the non-Chinese population?
A. The results may not apply to non-Chinese patients because:
· Chinese have a much higher prevalence of intracranial large-artery atherosclerosis than whites, and the intermediate prevalence of blacks and Hispanics
· Chinese have a different prevalence of genetic polymorphisms of liver cytochrome P-450 (CYP) isozymes, which metabolize clopidogrel to its active metabolites
· CHANCE and POINT subjects likely will have different risk factor profiles
· CHANCE and POINT subjects likely will have a substantially different profile of access to effective secondary stroke prevention
· It is surprising that while the total stroke rate in CHANCE was (515/5170=) 10%, the total cardiovascular death rate was only (11/5170= 0.2%) and the overall death rate was (20/5170=) 0.4%. The overall death rate in Northern California Kaiser was 2.6% (Johnston et al. JAMA 2000;284:2901-2906). There were 515 strokes in CHANCE and only 11 cardiovascular deaths, a very low stroke mortality rate.
The NINDS-appointed Data Safety and Monitoring Board reviewed all data, including the CHANCE results, and recommended POINT continue as planned. All IRB’s have confirmed it should be continued.
3.Q. How can we continue to enroll subjects in POINT now that the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial has reported that among patients with reent lacunar strokes, addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death?
A. The result does not affect POINT and our DSMB continues to carefully monitor the safety and efficacy of this intervention in POINT. POINT is an acute trial while SPS3 was not.
POINT FAQ 1 addressed our justification for testing dual antiplatelet treatment in view of the MATCH trial results (and others) showing increased risk of hemorrhage in patients receiving dual treatment (see the detailed justification in FAQ 1.Q.
In brief, trials of clopidogrel in combination with aspirin after stroke/TIA suggest that the combination reduces the risk of stroke but increases the risk of major hemorrhage. However, in POINT we expect the risk of thrombosis to be high in the acute period after TIA and minor stroke and the risk of hemorrhage to be lower compared to the subjects with infarcts of moderate or large size enrolled in other trials (e.g., MATCH and SPS3). Thus, the combination of clopidogrel-aspirin may be particularly effective and relatively safe in patients with TIA and minor ischemic stroke.
Following its regular September 30, 2011 meeting, the POINT DSMB recommended that all sites encourage their subjects to use the lower dosage of aspirin daily, based on the interim results of the SPS3 and other trials. As per the protocol, POINT continues to recommend 162mg for the first 5 days and 81mg daily thereafter for the remaining 85 days.
4.Q. Please clarify the definitions of TIA and stroke for the POINT trial. If a patient has symptoms at the time of randomization, but recovers to normal by 24 hours, is he/she considered a stroke or a TIA patient? Also, if a patient fully recovers by the time of randomization, but later has an MRI showing restricted diffusion, is he/she considered a stroke or a TIA patient?
A. It is important to begin by describing the primary objective of the POINT Trial: to determine whether clopidogrel is effective in improving survival free from ischemic vascular events at 90 days when initiated within 12 hours of onset of high-risk TIA or minor ischemic stroke in patients receiving aspirin. The primary analysis of the trial will not distinguish between subjects with high-risk TIA and minor stroke. So in some respects the distinction between high-risk TIA and minor stroke at entry is not critical. However, we will distinguish the two groups for secondary analyses evaluating the impact of therapy on risk of major systemic or intracranial hemorrhage separately.
POINT will use the tissue-based definition of stroke and TIA. TIA is a transient episode of neurological dysfunction caused by focal brain ischemia, without acute infarction. An ischemic stroke is a cerebral infarction, demonstrated by imaging or clinical features. Some infarcts cannot be visualized, even with state-of-the-art imaging techniques. Therefore, in some situations, the diagnosis of an ischemic stroke will be rendered on the basis of clinical features despite the lack of imaging confirmation; for example, prolonged deficits lasting several days and a clinical syndrome consistent with an infarct. In other situations, the imaging study is performed too soon to identify tissue injury; for example, a patient may present with a clinical syndrome typical of a stroke and have a CT scan performed, especially within the first few hours, that does not reveal acute ischemic abnormalities. If the symptoms persist, the patient is left with permanent neurological disability, and no follow-up imaging studies are performed, a diagnosis of ischemic stroke can be inferred.
For the purposes of defining the index ischemic events for trial entry, we will use the diagnosis given to each subject at the time of randomization based on all of the information available at that time. For example, a subject whose symptoms have completely resolved by the time of randomization who has not had any imaging studies suggestive of infarction will be considered a TIA patient. In contrast, a subject whose symptoms have resolved, but who has an MRI demonstrating acute infarction prior to randomization will be considered a stroke. Any subject who has continuing symptoms at the time of randomization will be considered a stroke patient.
In considering the diagnoses of TIA and minor stroke in secondary analyses for safety, POINT will use further information gathered after the initial entry diagnosis to adjudicate whether the subjects had a TIA or stroke. In the case of subjects who were initially diagnosed with TIA because symptoms had resolved by the time of randomization, but who had an MRI scan performed after randomization demonstrating acute infarction, they will be adjudicated as stroke for the purposes of this secondary analysis. Any patient initially diagnosed with stroke who does not have further brain imaging with evidence of infarction, but who does have complete resolution of symptoms within 24 hours will be considered TIA.
For the purpose of adjudicating outcome events, we will continue to use the tissue-based definition of TIA. If a subject has rapid resolution of symptoms, and no brain imaging suggesting tissue infarction, he/she will be considered to have had a TIA. Any brain imaging evidence of infarction or clinical evidence (such as ongoing symptoms) will qualify the event as having been stroke. Again, any patient initially diagnosed with stroke who does not have further brain imaging with evidence of infarction, but who does have complete resolution of symptoms within 24 hours will be considered TIA.
5.Q. Regarding the time window for enrollment, when a potential subject wakes up with his/her neurologic deficit, how do we define the time of symptom onset? Can we use the patient’s self report?
A. As for acute stroke trials and care, please use the last known time free of new ischemic symptoms as the time of onset. In the case of a patient with symptoms upon waking, this may be prior to going to sleep. Self report is acceptable.
6.Q. The protocol states that “a trained licensed physician investigator will be required to confirm the diagnosis of TIA or minor ischemic stroke and to calculate the ABCD2 score and NIH Stroke Scale score.” Does this have to be the PI or co-PI, or can it be a sub-investigator? Is an MD required?
A. A physician (MD or DO), PA or NP investigator must confirm eligibility and review the calculation of the NIHSS and the ABCD2 score either in person or by phone with a properly trained and certified non-physician investigator prior to randomization into the study. The protocol will be modified to reflect this change.
7(a).Q. A patient comes in to the ED with a moderate to severe syndrome BUT over the next few hours (without tPA) improves to a 2 and stays there. This seems like a good patient but if he/she waxes/wanes how long do you want the patient to have an NIHSSS < 3 before we enroll?
A. The patient needs to be at an NIHSS ≤3 at the time of randomization, but for no set time period. If the patient is still within the 12 hour time window when he/she improves to NIHSS ≤3, then the patient can be enrolled.
7(b).Q. In addition, if we are working toward enrollment and obtain consent and the patient changes a bit: normal to NIHSS=2 or the opposite. –the patient still meets criteria BUT has changed which “group” he/she is in – does that matter?
A. Unless there is a contraindication to enrollment (i.e., they are now a candidate for tPA), then they can still be enrolled in the trial. Their status at the time of randomization (TIA or Minor Stroke) should be the recorded initial event.
8(a).Q. A patient's presentation looks like a capsular warning syndrome – waxing and waning. Can we enroll the patient when normal?
A. Yes, even if their NIHSS is 1, 2 or 3.
8(b).Q. How long should the patient be normal or NIHSS < 3 before we enroll?
A. There is no set time period that the patient needs to be at NIHSS ≤3, but he/she needs to meet the criteria at the time of randomization.
8(c).Q. How would we deal with this if we gain consent and the patient worsens to an NIHSS of 4 prior to randomization?
A. If the patient has not yet been randomized, and NIHSS worsens to a 4, then the patient does not meet eligibility criteria to be enrolled regardless of consent. The time of enrollment is at the time of randomization, so the patient needs to meet all eligibility criteria at that time.
If the patient has already been randomized, he/she should still receive the treatment, as long as there is no contraindication. We would like to minimize the time from randomization to drug administration (ideally <5 minutes) to avoid this scenario as much as possible.
9.Q. Do patients in the ED need to have a swallow screen done prior to enrollment since the inability to swallow is part of the exclusion criteria?
A. Clinical judgment should be used to decide when a swallow screen is needed. It should not be necessary in patients presenting with TIA. We recommend screening swallow studies for patients presenting with stroke, as per guideline recommendations.
10.Q. If a patient cannot give informed consent for themselves but a Legally Authorized Representative is present, can the representative provide consent?
A. No. Any patient who cannot provide informed consent personally is excluded from the trial.
11.Q. If patients are already on clopidogrel (or dual antiplatelet therapy with clopidogrel and aspirin), can they be enrolled in POINT (assuming that then their open-label clopidogrel would be stopped and they would get just study drugs)? (Updated 10-26-16)
A. Yes. The loading dose of clopidogrel should not be dangerous even if a patient was previously on clopidogrel. In addition, in cases where long term clopidogrel is not indicated (which would be an exclusion criteria) it is reasonable to treat with aspirin alone and therefore ethical to enroll in the trial. If, however, the treating physician feels concerned about the extra doses or about the possibility that the patient will be randomized to aspirin alone, he or she should not enroll the patient.
Also see FAQ 15.Q.
12.Q. If a patient is taking clopidogrel prior to the study, and is randomized to placebo, what are the potential harms, and how should we deal with them? (Updated 10-26-16)
A. Enrollment is a choice. If a physician or patient feels that clopidogrel is strongly indicated, that patient should not be enrolled in the trial, as is stated in the protocol. However, most experts believe it is ethical and acceptable to stop clopidogrel and treat with aspirin. Studies suggest that adherence to less expensive drugs is greater, providing rationale for a switch in some patients. Also, clopidogrel has never been studied acutely after stroke or TIA in a non-Chinese population, whereas aspirin is beneficial in this setting as observed in the IST and CAST trials.
13.Q. What should we know about the new FDA MedWatch report related to clopidogrel?
A. In January 2009, the FDA released a MedWatch report regarding clopidogrel (Plavix®), notifying healthcare professionals that “the makers of Plavix have agreed to work with the FDA to conduct studies to obtain additional information that will allow a better understanding and characterization of the effects of genetic factors and all other drugs (especially the proton pump inhibitors (PPIs)) on the effectiveness of clopidogrel. FDA is aware of published reports that clopidogrel (marketed as Plavix®) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel or that using certain other drugs with clopidogrel can interfere with how the body metabolizes clopidogrel.” In March 2010, a black box warning was added to the label for clopidogrel: “Reduced effectiveness in patients who are poor metabolizers of the drug – that some patients do not convert Plavix to its active form as well as other patients. These patients may not get the same benefit from Plavix and are known as poor metabolizers.”
There are currently no new recommendations for use of clopidogrel, except that healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI in patients taking clopidogrel. For this reason, PPIs are discouraged in patients enrolled in POINT, and these patients should be evaluated for the appropriateness of other agents, such as H2 blockers.
14.Q. How do I give the patient the loading dose of the study drug and the further study pills?
A. The study drug bottle will contain 97 tablets. Once a patient is randomized, and a study drug bottle is obtained, the patient should immediately be given 8 tablets from the bottle to be taken at that time as the loading dose. The patient will then have 89 tablets remaining, and should be instructed to take one tablet per day for the next 89 days. The patient will also be given an information sheet and a calendar along with the study drug.
15.Q. If a patient is believed to need to take a proton-pump inhibitor (PPI) or another medication for gastroesophageal reflux disease (GERD), are there any guidelines for which medications should be used?
A. PPIs are discouraged in patients enrolled in POINT. If a patient is judged to need a medication for gastroesophageal reflux disease, the preferred medications would be H2 blockers, such as famotidine 20mg twice daily, or ranitidine 150mg twice daily. If a patient is judged to require treatment with a PPI during enrollment, and is not believed to be a candidate for another medication such as an H2 blocker, the first choice of PPI agent would be pantoprazole 40mg daily.
A. Yes. Since we are giving a loading dose of clopidogrel and this is our major intervention, the patient should be given the full dose (8 pills) of study drug in the ED regardless of whether or not he/she took a home dose of clopidogrel.
Re-loading patients already taking clopidogrel with clopidogrel 300-600mg is the convention of cardiologists in the United States and in Europe for treating patients with acute coronary syndromes (ACS). There is substantial evidence supporting the safety of this approach in that setting although few data exist for TIA/minor stroke patients. (Williams DO, Abbott JD. What to do with patients receiving long-term clopidogrel: reload or relax? Circulation. 2008; 118(12): 1219-22)
Also, see FAQ 10.Q. under Randomization and Enrollment, and FAQ 41.Q. under Post-Enrollment Outcomes and Events regarding accidental or purposeful overdose of study drug.
17.Q. If a patient was taking aspirin prior to enrollment, and already has taken a dose on the day of presentation, should the patient still be given a dose of aspirin on enrollment?
A. While the dose of aspirin during enrollment is 50-325mg daily, at the discretion of the treating physician, the strongly recommended dose is 162mg daily x 5 days followed by 81mg daily. If a patient has already taken some aspirin within the 12 hours prior to presentation, POINT suggests supplementing the prior dose to meet the above guidelines. For example, if a patient has taken a dose of 81mg within 12 hours of presentation, he/she should be given another 81mg. After enrollment, the second dose of aspirin should be scheduled along with the study drug so that both are administered ≤ 24 hours after the loading dose of study drug. Routine use of aspirin doses of 325 mg is common and the intent is to reduce the risk of subtherapeutic drug levels early on since the risk of thrombotic events is highest soon after the index event. See FAQ 30 for information on the timing of the second dose of study drug.
18.Q. When is a patient officially in the trial – at consent signing? At randomization? Or at taking the first pills?
A. The patient is officially enrolled at the time of randomization. Since things can change quickly in patients presenting acutely after TIA or minor stroke, it is essential that study drug be given immediately after randomization.
19.Q. When patients with stroke are admitted to the hospital, many times, they are placed on low-dose enoxaparin (Lovenox) or heparin for DVT prophylaxis. All heparins are listed as prohibited concurrent medications - does this include low-dose heparins for DVT prophylaxis?
A. Yes. Patients enrolled in POINT will not be allowed on any anticoagulation, including low-dose DVT prophylaxis. Given the types of patients that will be enrolled in POINT, this should not contradict any guidelines for the standard of care.
TIA patients and most patients with minor stroke (NIHSS≤3) do not require DVT prophylaxis. A Scientific Statement From the American Heart Association (Stroke 2009;40;2911-2944) states that early implementation of anticoagulant therapy or physical compression modalities should be considered for all stroke patients who cannot ambulate at 2 days and who are at risk for DVT or pulmonary embolus. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines: Antithrombotic and Thrombolytic Therapy for Ischemic Stroke, 8th Edition (Chest 2008;133;630S-669S) recommends prophylactic low-dose SC heparin or low-molecular weight heparins for acute stroke patients with restricted mobility. The JCAHO DISEASE-SPECIFIC CARE STROKE PERFORMANCE MEASURES for Stroke-01 state that patients with stroke who are non-ambulatory should start receiving DVT prophylaxis by end of hospital day two.
Most patients who score 2 or 3 on the Motor Leg component of the NIHSS (and therefore could benefit from DVT prophylaxis) will receive another point or 2 on the Motor Arm and therefore be ineligible for POINT enrollment. The few who do qualify and require DVT prophylaxis, can be treated appropriately with a sequential compression device. Those deemed to require anticoagulation must be excluded. Patients enrolled in POINT who experience an outcome stroke that requires anticoagulation for DVT prophylaxis must have their study drug stopped during the period of anticoagulation.
20.Q. If a candidate for enrollment in POINT is planning to have knee surgery that will require temporary discontinuation of study medication, is it still okay to enroll the patient.
A. Patients anticipating major surgery that may lead to cessation of study drug for more than 7-10 days should not be enrolled, especially if they may require other antithrombotics peri- or post-operatively. Parenthetically, major surgery is commonly associated with a period of procoagulability so a good case can be made for postponing elective surgery for some weeks following a cerebral ischemic event.
If a subject already enrolled in POINT requires temporary interruption of study medication for surgery or other therapy, the study drug will be resumed when it is considered safe by the subject’s physician.
21.Q. The POINT Manual of Procedures (MoP) states the initial (loading) dose of study drug must be taken in the presence of the PI or study team member. If it's not possible for ANY member of the team to actually witness the subject take the initial dose, may a nurse in the hospital witness the subject take the study drug and note this in the patient's hospital record?
A. As the time to treatment, rather than time to randomization, is the crucial element of POINT, the subject should take the first eight pills of the study drug (loading dose) while the study investigator or other study team member is present. The investigator must facilitate dispensing the medication and ensure it is taken within the 12-hour treatment window, (or as soon as possible within the subsequent 2 hours), recording the date and time of the dose in WebDCU (CRF 7: Index TIA/Stroke Symptoms). The time between randomization and treatment should be minimized: drug treatment should be considered STAT, administered in the first hour following randomization.
22.Q. If a patient receives heparin for DVT prophylaxis in the Emergency Department and then is found to be eligible for POINT, can the patient be enrolled since anticoagulants are prohibited medications?
A. Yes, but after enrollment anticoagulants are prohibited.
23.Q. The primary objective of POINT is to determine whether clopidogrel is effective in preventing major ischemic vascular events at 90 days when subjects are randomized within 12 hours of time last known free of new ischemic symptoms in patients receiving aspirin.
How do we determine when the clock starts on the “12 hours of time last known free of new ischemic symptoms”? Let’s look at a few examples.
1. A patient arrives with symptoms that began at 1pm, resolved at 3pm, and is being enrolled in POINT at 5pm.
2. A patient’s symptoms began at 1pm, she arrives at 3pm with an NIHSS score of 6 that improves to a score of 3 at 5pm, and is being enrolled in POINT at 5pm.
3. A patient went to sleep at 8pm feeling fine, but on awakening at 7am noticed ischemic symptoms. He presented to the hospital at 9am for treatment.
4. A patient went to sleep at 8pm feeling fine; however, on awakening at 7am noticed ischemic symptoms. The symptoms resolved completely in 30 minutes and she continued with her morning. At 11am she noticed recurrence of the ischemic symptoms and presented to the hospital at noon.
A. In the first example, the symptoms of this index TIA began at 1PM so that is when the “12-hour clock” begins; this subject is eligible for enrollment. Remember, some of these patients who appear to have TIAs will have an infarct on their subsequent MRI.
In the second example, a minor ischemic stroke, the same is true even if the patient’s NIHSS score fluctuates (in this case, from 6 to 3) during the interval between 1PM and 5PM. Since the subject’s symptoms of ischemic stroke began at 1PM, that is when the “12-hour clock” begins; the subject is eligible for enrollment.
In the third example, the time last known free of new ischemic symptoms was 8pm so this subject would need to have been randomized into the study before 8am the next day. He presented to the hospital that day at 9am, so this subject is not eligible for enrollment.
In the fourth example, the clock for the index event starts at 11am. Therefore, this subject is eligible for enrollment.
24.Q. There is confusion as to whether subjects are required to be enrolled or to be treated with study drug within 12 hours of the time last known free of new ischemic symptoms. Which is correct?
A. The protocol (v3.0) states that subjects must be randomized within 12 hours of the time last known free of new ischemic symptoms. Subjects always should receive their loading dose of study drug within 2 hours of randomization so the administration of study drug should be considered STAT.
25.Q. A patient was given clopidogrel 300mg at an outside hospital and then was transferred to us. May we consider this patient for enrollment in POINT, and do we give the full loading dose of study drug?
A. Yes, this patient may be enrolled and must be given the full loading dose of study drug. Studies have compared loading doses of 300mg, 600mg and 900mg of clopidogrel and found 900mg to be safe (Williams DO, Abbott JD. What to do with patients receiving long-term clopidogrel: reload or relax? Circulation. 2008; 118(12): 1219-22).
26.Q. Is Effexor a prohibited or discouraged medication in POINT?
A. Effexor (venlafaxine) is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SNRIs). From the perspective of the POINT trial, this class of drug is neither prohibited nor discouraged.
Under Precautions, rather than under Contraindications or Warnings, the Effexor label states,
"Abnormal Bleeding: SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation."
There may be other drugs that carry this precaution. POINT encourages its enrolling sites to consider the risk-benefit for individual patients of concomitant use of serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors and study drug before enrolling patients.
27.Q. Are patients with carotid or vertebral artery dissections excluded from POINT?
A. No. Arterial dissections are small tears in the intima of the arteries in the neck that may cause arterial thromboses. The majority of physicians now treat dissection patients with antiplatelet drugs, so these patients may well benefit from our study drug. However, some investigators prefer to anticoagulate dissection patients, so this is another reason to image the cervical arteries before enrollment in POINT.
28.Q. A patient with a minor stroke had an inguinal hernia repair 6 days ago. Is this a 'major surgery' that excludes the patient? The surgeon was okay with dual antiplatelet therapy.
A. A common definition of major surgery is any surgical procedure that involves general anesthesia or respiratory assistance. However, some surgeries may not use general anesthesia or respiratory assistance but be a substantial risk for bleeding while some new minimally invasive surgeries utilize anesthesia or respiratory assistance but are low risk for bleeding after a few days. Consequently, the surgeon should be asked if he/she believes treatment with aspirin plus clopidogrel is acceptable. If doubt remains about the patient's eligibility, he/she should be excluded.
29.Q. Is isolated facial weakness sufficient to count in the ABCD2 score in consideration for enrollment?
A. Yes. It is included under Unilateral Weakness.
30.Q. TIMING OF THE SECOND DOSE OF STUDY DRUG. If the loading dose of study is given early in the morning, should the second dose be given later that day or is it acceptable to wait until the next day and administer study drug along with other morning medications?
A. The second dose should be scheduled so that it is administered ≤ 24 hours after the loading dose. Loading doses of 900 mg of Plavix have been tested in clinical trials and found to be safe and the intent is to reduce the risk of subtherapeutic drug levels early on since the risk of thrombotic events is highest soon after the index event.
For example, the follow schedules would all be acceptable:
Loading dose, Day 1, 8 am
Second dose, Day 1, 9 am (1 hour after loading dose)
Next dose, Day 2, 9 am
Loading dose, Day 1, 5 am
Second dose, Day 1, 6 pm (13 hours after loading dose)
Next dose, Day 2, 9 am
Note: The above examples may result in the participant completing the course of study drug one day early.
However, the following schedule would not be acceptable because there is a > 24 hour gap between the loading dose and the second dose:
Loading dose, Day 1, 8 am
Second dose, Day 2, 9 am (25 hours after loading dose)
Next dose, Day 3, 9 am
31.Q. A POINT subject wants to take NSAIDs 'intermittently' for arthritic pain. Should the subject discontinue the study drug permanently if treated with an NSAID? According to the protocol, the subject can take an NSAID short-term (<7 days) but the protocol doesn’t specify if the >7 days is overall or consecutive days treated. Also, is there a cutoff number of 'intermittent’ days of NSAID use that would make the subject ineligible to continue study drug?
A. Patients who cannot stop all NSAIDs for 90 days should not be enrolled in POINT, and the use of NSAIDs during the study is a protocol violation. If an enrolled subject decides he/she must use NSAIDs intermittently, and the treating physician believes there is a clinical need that justifies their added risk in the setting of study drug use, the NSAID should be employed for as short a time as possible, but not sooner than 8 days after randomization. CRF 18 (F18 Concomitant Medications) should be completed to record the use of an NSAID. The 7 days of acceptable use are intended to be consecutive, while study drug is withheld. Subjects should be encouraged to use acetaminophen instead of an NSAID as it is often effective, or at least helpful. Also, they should be reminded that 90 days is a short time and we are trying to prevent their having a stroke.
32.Q. A site enrolled a subject who was assigned a study drug bottle number by WebDCU™. However, the subject was mistakenly given a bottle with a different number and the loading dose was taken from that bottle. The site submitted a formal protocol violation report to POINT and its local IRB but asked how to proceed with the subject at this time.
A. Under this unusual circumstance, the subject should continue to take the study drug from the bottle that was mistakenly given. This bottle needs to be damaged in WebDCU™ so that it is not assigned to a subsequent subject. The site also should contact their NETT or CRC Study Manager and a POINT Data Manager, as some additional steps are required. NOTE: Sites should use the POINT Randomization Verification Form, which is designed to minimize this type of error by documenting that the study drug ID on the bottle matches the number on the bottle retrieved from the site’s inventory.
33.Q. Is a patient who presents with sudden vision loss caused by a central retinal artery occlusion eligible for enrollment in POINT?
A. No. According to the protocol, the primary inclusion criterion for POINT is a neurologic deficit (based on history or exam) attributable to focal brain ischemia. Clinical outcomes in POINT are different. Again according to the protocol, an outcome ischemic stroke is defined as, “An acute focal infarction of the brain or retina (and does not include anterior ischemic optic neuropathy (AION)).”
34.Q. If a patent with a pre-existing neurologic deficit (e.g., facial weakness from a Bell's palsy) presents with a stroke, does the old deficit count in scoring of the stroke deficit? (New 10-26-16)
A. Yes. The NIH Stroke Scale was designed to “score what you see, not what you think,” so all pre-existing deficits are included. This helps to assure consistency across all categories of raters, since not all raters might know how to “subtract” out the pre-existing deficit.
We realize that a pre-existing Bell’s palsy could be contralateral to the new stroke-related weakness and therefore be simple to “subtract out.” Nevertheless, the NIHSS is a tried-and-true validated instrument that we do not want to modify just for POINT.
35.Q. Although use of tPA is an exclusion for entry into the POINT, if a patient is already enrolled and treated with the loading dose of clopidogrel/placebo plus aspirin, and then develops a new or worsening stroke, can he/she be treated with tPA?
A. Yes. The SITS (Safe Implementation of Treatments in Stroke) investigators created a 15-point Symptomatic ICH (SICH) score, the SITS SICH risk score, for predicting ICH after giving tPA (see Table 2 in Stroke. 2012;43:1524-1531). Aspirin added 2 points of 15 to the risk of SICH and about half of patients in POINT will already be on aspirin before enrollment, and more will receive it in the Emergency Department. Use of clopidogrel added 1 additional point. The investigators concluded, "We cannot propose withholding treatment with alteplase in patients otherwise eligible according to current guidelines." Also see Arch Neurol. 2008;65:607-611 and 575-576.
In the Third International Stroke Trial (Lancet 2012; published online May 23), 51% of the tPA-treated subjects were treated with 'antiplatelet drugs' in the previous 48 hours, it was 40% in the NINDS rt-PA Stroke Study, and there was a slight trend toward a greater benefit in this group for the primary endpoint---the proportion of patients alive and independent at 6 months.
Given this information, POINT recommends that patients who meet all POINT criteria for enrollment be enrolled and administered study drug and aspirin promptly. If they subsequently develop a new or worsening stroke and meet guidelines for tPA treatment, they should be given tPA. Patients and families should be told that pre-existing use of anti-platelet therapy might slightly increase the risk of symptomatic ICH. Although this will be considered a protocol deviation, we recognize that optimal individual patient management may dictate protocol deviations from time to time.
36.Q. How do we differentiate worsening of a minor stroke from occurrence of a new stroke?
A. For the purposes of the trial, we ask that all cases of worsening after enrollment be reported as a stroke outcome event. These events will be adjudicated centrally, but only if they are reported. Head imaging should be performed if clinically indicated. It should be clear in the judgment of the investigator that definite worsening occurred, even if the event is mild worsening of a sensory, articulation, or coordination deficit. If you are not sure, don't report it. In the end, we want real strokes- mild, moderate and severe.
Multiple fluctuations, for example presenting with an NIHSS of 6 that improves to 2 at the time of enrollment, but a few hours later reverts back to NIHSS of 6, should be reported as a new stroke. One of the things we are testing is if dual antiplatelet treatment can prevent this "fluctuation" from progressing to stroke better than aspirin alone.
Study drug then should be continued unless there is a contraindication.
37.Q. If a patient is randomized and receives study drug, and is later found to have severe carotid stenosis, how should we proceed with surgery? Is there a specific amount of time that they should be off of study drug before intervention? How long should they remain off of study drug?
A. Ideally, carotid imaging will be done in the ED so that severe carotid disease can be diagnosed prior to study enrollment (this would be an exclusion criteria). If that is not possible and the patient is diagnosed with symptomatic carotid stenosis after enrollment and is felt to be a surgical candidate, then the study drug should be discontinued for the shortest time period judged safe by the treating physician. Study drug should resume as soon as it is judged safe by the treating physician. Unblinding should only occur when it is judged to be absolutely necessary from the standpoint of clinical decision making.
A loading dose of clopidogrel is not a contraindication to carotid surgery or angioplasty/stenting, though the risk of bleeding at the surgical/puncture site will be increased.
38.Q. If a patient is randomized and receives study drug, and then is discovered the following day to have severe carotid stenosis, and the interventionist asks to have the study treatment unblinded, what should we do? If the patient is not on clopidogrel the interventionist wants to load the patient, and if the patient is on clopidogrel she wants to avoid double loading.
A. Ideally, carotid imaging (CTA, MRA or Ultrasound) will be done in the ED so severe carotid disease can be diagnosed prior to study enrollment (this would be an exclusion criteria). If that is not possible, and the patient is diagnosed with symptomatic carotid stenosis after enrollment, it is appropriate to unblind the study treatment. They should return to taking study drug as soon as it is believed by the treating physician to be safe. Unblinding should only occur when it is felt that it is absolutely necessary from the standpoint of clinical decision-making and only those directly involved in the care of the subject should be given the unblinded treatment assignment..
39.Q. Is it necessary to withhold study drug in preparation for a procedure, e.g., stenting?
A. Study drug should only be held if it is judged to be necessary by the treating physician, and should be discontinued for the shortest time period judged safe and the subject should resume drug as soon as it is judged to be safe by the treating physician, surgeon or interventionist. Clopidogrel is not a contraindication for many procedures (including most stents), but may increase the risk of bleeding at the intervention site. Non-urgent procedures that are contraindicated on clopidogrel should be postponed until the study conclusion if it is judged to be safe.
40.Q. Is there a relevant time period to abstain from becoming pregnant for study purposes? For example, is it okay for someone to become pregnant immediately after the study is over?
A. POINT recommends 95 days (5 days after the last dose of study drug) to be completely safe.
41.Q. Is a 90-day follow-up CT or MRI required for the POINT study? How about for "outcome event" patients?
A. There is no requirement for follow-up brain imaging in the study. If someone has had a suspected cerebrovascular outcome event (stroke, TIA, intracerebral hemorrhage, or other intracranial hemorrhage), then brain imaging (either CT or MRI) is strongly encouraged at the time of the event, but not required. In this case, imaging is considered standard of care in the U.S.
42.Q. We enrolled a subject into POINT. When she was admitted to the hospital and sent to the floor, 5000 units of sc heparin were administered inadvertently for DVT prophylaxis. Is this a protocol violation even though this was an error and no additional heparin was administered?
A. Yes. The heparin must be recorded as a prohibited medication on ‘Case Report Form 18: Concomitant Medications’ and it will be documented as a protocol violation.
A similar question involved a subject who took two doses of Advil for a headache. This too is a protocol violation. Subjects should be reminded that NSAIDS are prohibited medications for the 90 days of the trial and be encouraged to substitute acetaminophen.
43.Q. We enrolled a subject in POINT and then obtained an MRA that demonstrated a 50% intracranial artery stenosis proximal to the symptomatic brain territory. Some members of our team want to unblind the subject’s POINT treatment and if the subject is on aspirin only, start the patient on clopidogrel too. Is this okay?
A. This patient is exactly the type we want in POINT. There is no evidence clopidogrel is beneficial and safe in this setting. If your team feels that the indication for clopidogrel is established in such patients, we strongly encourage you to screen for intracranial stenoses before randomization.
Each unblinding is a really big issue for the trial. The problem doesn’t just stop with the person receiving the information: he/she will act on the information, so there may be a crossover in treatment and also anyone else seeing that the patient’s assignment was unblinded would identify a subsequent protocol violation (or lack thereof) and know what the treatment assignment was. It’s a big deal. Our DSMB is notified immediately and also will be unhappy.
44.Q. We enrolled a subject in POINT and over the subsequent few days he developed painful ecchymoses, with some overt bleeding, on his arms. He was worried and wanted to stop the study medication. What do you suggest?
A. As the Plavix Package Insert recommends, inform patients that they will bruise and bleed more easily and will take longer than usual to stop bleeding (and should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine). Painful or serious skin bleeding is rare on treatment with aspirin, clopidogrel, or aspirin plus clopidogrel. POINT recommends that subjects first try to continue with the study drug and take only 81 mg of aspirin daily. If that fails, try to switch to every‑other‑day dosing for 10 days until all residual effects of the loading dose of study drug have abated and then resume daily dosing, and only if the painful or intolerable ecchymoses continue, discontinue the study drug.
45.Q. Is it true that Coenzyme Q-10 may cause bleeding, or even decrease the effectiveness of clopidogrel, and therefore be a potential hazard for subjects in POINT?
A. MedlinePlus is a service of the U.S. National Library of Medicine and the NIH. It provides an excellent review of the status of Coenzyme Q-10’s putative benefits and risks. You will notice, based on scientific evidence, that no indication receives an “Effective” rating. Coenzyme Q10 appears to be generally safe with no significant side effects, except occasional stomach upset. Its safety during pregnancy and breastfeeding is unknown and, therefore, should not be used during that time until more information is available. The document states Coenzyme Q-10 may affect warfarin dosing because of possible effects on the clotting system. Coenzyme Q-10 is a 1,4-benzoquinone with a chemical structure similar to vitamin K. The document does not flag for attention interactions with any antiplatelet drugs. We are aware of no known reports of bleeding from CoQ10.
If individual subjects or treating physicians are concerned about detrimental effects of Coenzyme Q-10 use in POINT subjects, they can consider discontinuing it for the three months of the trial.
46.Q. Is the cost of the aspirin covered by the study grant or is it billed to the patient?
A. The manufacturer, Sanofi-Aventis, is providing clopidogrel and its placebo for the study. Aspirin will be provided by the patient or the patient's treating medical facility. It's important to remember that Aspirin is not a study drug, and the dose is determined by the treating physician.
47.Q. One of our neurologists learned that a patient who was on aspirin and had a minor stroke was entered into POINT. The next day he became the patient’s neurologist and insisted that the patient was “an aspirin failure” so he withdrew the patient from POINT and started him on clopidogrel. Is this okay?
A. Aspirin for primary prevention of serious vascular events is of uncertain net value, as the reduction in occlusive events needs to be weighed against any increase in major bleeds (Lancet 2009;373: 1849–60 & Stroke. 2011;42:227-276; page 249). Aspirin for secondary prevention reduces the risk of these events by about 20% compared to placebo. Thus the majority of stroke-prone patients on aspirin will have their stroke in spite of treatment. There is no evidence that modifying the aspirin treatment (to a different dose or drug) after brain ischemia is better than maintaining it. See the below FAQ addressing the new AHA/ASA guidelines regarding this matter.
A. Sanofi-aventis informs us they are aware of no serious consequences of a clopidogrel overdose and increased risk of bleeding is the only known potential concern. In case of bleeding, fresh platelet transfusion may be considered as an option to reverse the effect. We recommend stopping study drug, monitoring the subject closely, maintaining the treatment blind, and resuming the study drug in one week.
Regarding prevention of accidental overdoses, we recommend that sites verbally request subjects’ understanding and repetition of study drug regimen at the time of enrollment and again at the Day 7 telephone follow-up, highlight or use brightly colored labeling on drug bottle dosing information and that subjects be given a study drug calendar with the dosing requirements for 90 days, and be encouraged to review it daily.
49.Q. I have a patient who needs gastroprotection. I realize that use of proton-pump inhibitors (PPIs) in POINT is discouraged and that histamine-receptor (H2) antagonists should be used if drug treatment is necessary. However, the H2-antagonist cimetidine (Tagamet®) is also a discouraged medication. What H2-antagonist should I prescribe?
A. It is true that PPIs and cimetidine can interfere with conversion of clopidogrel, a prodrug, to its active metabolite perhaps especially in subjects who are carriers of CYP2C19 loss-of-function alleles.The clinical implications of this finding remain uncertain; hence these medications are discouraged but not prohibited drugs in POINT. Even the H-2 antagonist ranitidine may have some inhibitory effect; famotidine or nizatidine may be the best choices.
50.Q. Is it ok to obtain platelet function assays on POINT subjects?
A. No. All subjects should be on aspirin and there is no compelling evidence to support modifying aspirin dosing based on the results of platelet function tests.
Assays for clopidogrel effects on platelets are strictly prohibited, as this is a double-blind trial and platelet function testing can unblind the study drug.
51.Q. A subject ingested the loading dose of study drug and vomited shortly thereafter. She said if she ingested a little food she could take the pills again and keep them down. Should we reload her with 8 more pills?
A. No. This has been a rare occurrence in POINT. A subject may vomit immediately and all of the study pills are visible in the vomitus. Others may vomit a variable time after ingestion and the pills are more or less visible. Sometimes the pills have dissolved completely but may or may not have been absorbed. Finally, each subject receives exactly 97 study pills necessary to complete the trial. Therefore, when all risks and benefits for the subjects and the POINT trial are taken into account, reloading should not occur.
52.Q. Certain sites are requesting a copy of the DSMB plan in order to submit the POINT Trial to their IRB.
A. Most NINDS DSMBs do not have charters, and instead are asked to follow the NINDS Guidelines for Data and Safety Monitoring.
53.Q. Will the new AHA/ASA guidelines on stroke prevention in TIA and stroke patients affect the POINT trial?
A. No. The new guidelines published on January 1, 2011 (Stroke. 2011;42:227-276; page 249) state:
Recommendation 2. “Aspirin (50 mg/day to 325 mg/day) monotherapy, the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily, and clopidogrel 75 mg monotherapy are all acceptable options for initial therapy.”
Recommendation 5. “For patients who have an ischemic stroke while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered, no single agent or combination has been studied in patients who have had an event while receiving aspirin.”
54.Q. A patient was enrolled in POINT who initially passed a swallow test but later was unable to swallow pills while still able to swallow apple sauce and liquids. Is it acceptable to crush the study medication and give with something ingestible by the subject?
A. Inability to swallow medications is an exclusion criterion. Even if a patient can swallow crushed medication, if the inability to swallow pills is a chronic condition that will persist for the duration of the trial, that patient should be excluded. However, subjects already enrolled who develop difficulty swallowing whole pills can crush them until they recover the ability to swallow pills.
There are websites that state Plavix® tablets should not be crushed. For example, “you better not crush the tablet. The tablet is coated with a layer of wax which determines its dissolving rate in your stomach and intestine, if you crush the tablet, the wax layer will be destroyed and the release rate of the drug may not be uniform, leading to possible side effects.” There are no data to support this assertion, no reports of side effects, and no good rationale to think side effects are a concern. It is not contraindicated by the Plavix Package Insert. The worst likely side effect would be delayed absorption and this is better than the alternative of withholding the study drug.
Both clopidogrel and ASA tablets can be administered via a gastric tube if the patient experiences swallowing difficulty. In addition, an aspirin suppository may be given as an alternative way to administer the ASA until the subject is able to swallow.
55.Q. In the case of a patient with blindness that precedes the onset of a minor ischemic stroke that causes the patient to be considered for POINT, is it necessary to add 3 points for blindness in the NIHSS as this will exclude the patient?
A. Yes, this patient must be excluded. The rationale is that a blind subject could experience a large occipital lobe infarction that is clinically silent. The NIHSS is a tried-and-true validated instrument that we do not want to modify just for POINT.
In the case of a patient with blindness that precedes the onset of a TIA, eligibility is left to the judgement of the investigator. If the patient is otherwise in good neurologic health such that future neurologic assessments will likely be reliable, enrollment is allowable.
56.Q. Several IRBs have asked questions about whether the FDA has approved clopidogrel, aspirin, or the combination of clopidogrel and aspirin for patients with TIA, rather than ischemic stroke; and, is the clopidogrel loading-dose of 600 mg approved. Can POINT provide guidance in answer to these queries?
A. Clopidogrel is approved by the FDA for use after ischemic stroke, but is not approved specifically for use after TIA. Consequently, neither is the combination of clopidogrel plus aspirin approved by the FDA. Clopidogrel is one of the antiplatelet drugs recommended by the American Stroke Association/American Heart Association and all other major USA and European guidelines. The purpose of the POINT trial is to determine if clopidogrel plus aspirin is more beneficial than aspirin alone in this population at high risk for thrombosis and presumably low risk for serious hemorrhage, because they have minimal brain damage. In addition, 300-600 mg is the current loading-dose recommendation by the American College of Cardiology/American Heart Association for acute coronary syndrome, an atherothrombotic disorder akin to acute TIA and minor ischemic stroke. There is no recommendation for acute minor brain ischemia and therefore POINT is being conducted.
The FDA status on aspirin is contained in its Final Rule: "The agency believes a dose of 50 to 325 mg is an effective daily dose for subjects with TIA or cerebral ischemia. Therefore, in this final rule, the agency is providing for a dosage of 50 to 325 mg aspirin daily (http://www.fda.gov/ohrms/dockets/98fr//102398c.txt)." The FDA is silent on clopidogrel for TIA as noted above, but all stroke prevention guidelines recommend aspirin, clopidogrel, or aspirin plus dipyridamole for prevention of stroke in patients after cerebral ischemia (stroke or TIA).
The FDA reviewed a summary of the POINT trial and waived any requirement for a New Drug Application (IND). If a site chooses to include this information in its consent form, they certainly may do so.
There were 1220 subjects enrolled in POINT when the NIH-appointed Data Safety Monitoring Board met on October 12, 2012 and concluded, "As no safety concerns were identified, the POINT trial should proceed as planned."