Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Variability in platelet response to a single daily dose of 150 mg enteric coated aspirin in a high risk population.

PURPOSE: Previous studies have reported inadequate anti-platelet effect in 0.4-35% of patients taking aspirin. Such studies have arbitrarily defined the terms "semi-responders", "non-responders" or "resistant" to variable doses of aspirin on the basis of absolute values derived from different ex-vivo platelet aggregation (PA) methods. Our objective was to define response to 150-mg dose of aspirin in terms of normally distributed values using an ex-vivo measure of PA in a population at high risk for vascular events. METHODS: We prospectively studied high risk patients with either established coronary artery disease (CAD) or stroke or transient ischemic attack (TIA) or peripheral vascular disease or with multiple atherothrombotic risk factors like diabetes plus one of the following-- hypertension, increased total cholesterol, cigarette smoking, micro-albuminuria, low-high density lipoprotein (HDL), family history of CAD and receiving single 150 mg dose of aspirin daily. PA was assessed by chronolog lumi-aggregometer (490-2D) using arachidonic acid (AA) reagent. RESULTS: 130 patients were studied. The response of subjects to aspirin followed a normal, bell shaped distribution curve with a mean and standard deviation (S.D.) of 13.1 +/- 4.4%. 3.1% patients had PA values more than 2 S.D. of the mean, hence termed as hypo-responders to aspirin while another 3.1% patients had PA values less than 2 S.D. of the mean, hence termed as hyper-responders to aspirin. CONCLUSION: There is minimal inter-individual variability in the response to aspirin when tested with AA as the reagent. The response to aspirin follows a normal Gaussian distribution. The prevalence of hypo-responders to aspirin in high risk population is only 3.1%. This is the first study to document "hypo" and "hyper-responders" to single daily dose of 150 mg aspirin. The clinical relevance of these findings remains to be determined.

Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events: data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial.

BACKGROUND: Platelet inhibition at the time of a percutaneous coronary intervention has consistently been shown to decrease the risk of thrombotic adverse events but not restenosis. The role of enhanced antiplatelet protection through pretreatment with the platelet ADP-receptor antagonist ticlopidine in preventing both the early and late complications of coronary stenting has not previously been explored. METHODS AND RESULTS: In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, approximately 1600 patients were randomized to stenting with either placebo or abciximab in addition to aspirin and heparin. All stented patients also received ticlopidine after the procedure, but 58% of these patients were given ticlopidine before stenting at the discretion of the investigating physician. Among patients randomized to placebo, ticlopidine pretreatment was associated with a significant decrease in the incidence of the composite end point of death, myocardial infarction, or target vessel revascularization (TVR) at 1 year (adjusted hazard ratio, 0.73; 95% CI, 0.54 to 0.98; P:=0.036). Ticlopidine pretreatment did not significantly influence the risk of death or myocardial infarction in patients randomized to abciximab. Controlling for patient characteristics and for the propensity of being on ticlopidine, Cox proportional hazards regression identified ticlopidine pretreatment as an independent predictor of the need for TVR at 1 year (hazard ratio, 0.62; 95% CI, 0.43 to 0.89; P:=0.010) in both placebo-treated and abciximab-treated patients. CONCLUSIONS: In the EPISTENT trial, among patients randomized to stenting, starting ticlopidine before the percutaneous coronary intervention was associated with a significant decrease in the incidence of the 12-month composite end point for patients not receiving abciximab and the need for TVR among all patients.

Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention.

BACKGROUND: Although the effectiveness of abciximab (c7E3 Fab; ReoPro) in large populations of patients undergoing a percutaneous coronary intervention has been consistently proved in clinical trials, it is unknown whether all patients achieve and maintain target inhibition during treatment. Diabetic patients in particular are a subgroup of patients with known underlying platelet abnormalities whose long-term response to abciximab has been shown to vary from that of nondiabetic patients. METHODS AND RESULTS: Forty-nine diabetic and 51 nondiabetic patients who received adjunctive abciximab therapy during percutaneous coronary interventions were evaluated prospectively. The degree of platelet function inhibition was determined immediately after the abciximab bolus, 8 hours after the bolus (during the 12-hour abciximab infusion), and the next morning (13 to 26 hours after the bolus) with the use of a rapid platelet function assay (Accumetrics). After the abciximab bolus, platelet function was inhibited by 95+/-4% (mean+/-SD). By 8 hours, the average percent inhibition had decreased to 88+/-9%, with 13% of patients with <80% inhibition. The next morning (mean 19 hours after the bolus), mean inhibition was 71+/-14%. A difference was not found between diabetics and nondiabetics, nor was any physiological parameter found to be predictive of the response to abciximab. CONCLUSIONS: Although the majority of patients achieve and maintain >/= 80% platelet inhibition during the 12-hour infusion with standard-dose abciximab, there is substantial variability among patients. Diabetic status does not appear to influence this variability.

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study.

BACKGROUND: The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. METHODS AND RESULTS: Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACES: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve >/=95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P=0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those >/=70% inhibited (P=0.009). By multivariate analysis, platelet function inhibition >/=95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P=0.04). CONCLUSIONS: Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions.

OBJECTIVES: This study sought to determine whether the duration of pretreatment with the adenosine diphosphate receptor antagonist ticlopidine prior to intracoronary stenting is associated with the incidence of procedure-related non-Q-wave myocardial infarctions (MIs). BACKGROUND: Dual antiplatelet therapy with ticlopidine and aspirin is routinely used with stenting, although ticlopidine is commonly not begun until the day of the procedure. Periprocedural MIs are at least partially platelet-dependent events. As the maximal platelet inhibitory effects of this drug take 2 to 3 days to be realized, we hypothesized that longer treatment prior to stenting would be associated with lower rates of procedure-related MIs. METHODS: We reviewed outcomes in 175 consecutive patients treated with ticlopidine prior to stenting at the Cleveland Clinic Foundation. Those patients with an elevation in creatine kinase above our laboratory normal (>210 IU/L) with > or =4% MB fraction on routine evaluation were defined as having a non-Q-wave MI. RESULTS. There were 28 patients (16%) who had a non-Q-wave MI. Longer duration of ticlopidine pretreatment was strongly associated with a lower incidence of procedure-related non-Q-wave MIs (duration of pretreatment <1 day, 29% had MI; 1 to 2 days, 14%; > or =3 days, 5%; chi-square for trend=9.6; p=0.002). Ticlopidine pretreatment of > or =3 days was associated with a significant reduction in the risk of non-Q-wave MI (unadjusted odds ratio 0.18, 95% confidence interval=0.04 to 0.78, p=0.01) compared with pretreatment of <3 days. CONCLUSIONS: Among patients undergoing intracoronary stenting, beginning ticlopidine therapy several days prior to the procedure is associated with a reduced risk of procedural non-Q-wave MIs.

Variability in response to aspirin: do we understand the clinical relevance?

Aspirin, an irreversible inhibitor of platelet prostaglandin synthase activity, is the cornerstone of therapy for acute coronary syndromes. In recent years, laboratory and clinical data have accumulated that suggest there may be significant individual variability in the response to aspirin and that the effects of aspirin therapy vary significantly over time. There is, as of yet, no cohesive explanation for this variability. The term 'aspirin resistance' has been loosely applied to situations in which the clinical or ex vivo effects of aspirin are less than expected. In this review we discuss the clinical data regarding this phenomenon and the need for prospective evaluation of aspirin non-responders.

Uniform platelet activation exists before coronary stent implantation despite aspirin therapy.

BACKGROUND: Platelets play an important role in the natural history of coronary artery disease. Enhanced platelet aggregation and receptor expression unquestionably occur after coronary stent implantation; however, the functional characteristics of platelets before stenting have not been fully elucidated. METHODS: Platelets were assessed before intervention by platelet-rich plasma aggregation (PA) with 5 mmol adenosine diphosphate (ADP) and 1 mg/mL collagen; whole blood aggregation (WBA) by 1 mg/mL collagen; shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 126 patients undergoing elective coronary artery stent placement. All patients received aspirin for at least 7 days. The data were compared with those from 64 healthy volunteers. RESULTS: Each test revealed sustained platelet activation in patients undergoing coronary stenting compared with control values. These differences were significant for collagen-induced PA (P =.031); CF (P =.0001); expression of glycoprotein (GP) IIb/IIIa (P =.0001); P-selectin (P =.0008); platelet/endothelial cell adhesion molecule (PECAM)-1 (P =.0001); CD107a (P =.0001); CD107b (P =.0004); and CD63 (P =.009). CONCLUSION: Platelets are indeed activated before coronary stenting despite antecedent therapy with aspirin.

Inability of serum myocyte death markers to predict acute cardiac allograft rejection.

Acute cardiac rejection involves myocyte necrosis. Hence, markers of myocyte death may be useful in diagnosing rejection. Creatine kinase MB, MB isoforms, and troponins I and T were measured in 186 patients undergoing 365 endomyocardial biopsies. No differences were noted with rejection (rejectors vs. nonrejectors: CK=63.8 U/L and 86.6 U/L, P=0.0881; CK MB=2.04 ng/ml and 2.06 ng/ml, P=0.949; troponin T=0.134 ng/ml and 0.0881 ng/ml, P=0.374; troponin I=0.216 ng/ml and 0.707 ng/ml, P=0.357). The time course of troponins T and I levels in rejectors and nonrejectors do not differ with both groups having early elevations. Markers of myocyte death are inadequate predictors of acute rejection in cardiac allografts. The time course of troponins T and I suggests a possible role as prognostic indicators of outcome.

Antiplatelet agents in cardiology: the choice of therapy.

BACKGROUND: The platelet-rich, intracoronary thrombus is central to the pathogenesis of acute myocardial infarctions, unstable angina, and the majority of complications of percutaneous coronary interventions. Until recently, aspirin was the only antiplatelet agent available to help prevent or treat these events. Over the past several years, there has been a substantial expansion in our antiplatelet armamentarium as well as in our understanding of the clinical importance of antiplatelet therapy in limiting the complications of intracoronary thrombosis. Because of this, it is likely that over the coming years, the use of antiplatelet therapies will continue to expand, and it may not be unusual for a surgeon to encounter a patient being treated with two or even three platelet inhibitors. CONCLUSIONS: This review will highlight the benefits and limitations of the currently available antiplatelet regimens: aspirin, thienopyridines (ticlopidine and clopidogrel), and the platelet glycoprotein IIb/IIIa inhibitors.

Extracardiac vascular disease and effectiveness of sustained clopidogrel treatment.

OBJECTIVE: To assess the effectiveness of long term treatment with clopidogrel of patients with extracardiac vascular disease (ECVD) (a history of either peripheral arterial disease or cerebrovascular disease). DESIGN: Subgroup analysis of a prospective randomised clinical trial. SETTING: The CREDO (clopidogrel for the reduction of events during observation) trial was a randomised, double blind, placebo controlled trial conducted at 99 centres in North America from June 1999 through April 2001. PATIENTS: 2116 patients who were to undergo elective coronary intervention or were deemed at high likelihood of undergoing percutaneous coronary intervention were enrolled in the CREDO trial. The current study sample consisted of 272 patients with ECVD. MAIN OUTCOME MEASURE: One year incidence of the composite of death, myocardial infarction, or stroke in the intent to treat population. RESULTS: Patients with ECVD had a more than twofold greater relative risk reduction with clopidogrel for the primary end point compared with patients without ECVD (47.9%, 95% confidence interval (CI) -4.2% to 73.9%, v 18.2%, 95% CI -10.5 % to 39.5%, respectively). CONCLUSIONS: Longer term clopidogrel treatment provides added protection against thrombotic events throughout the arterial vasculature, not limited to the coronary arteries, and may be especially effective for patients with more diffuse atherosclerosis such as ECVD.

Clopidogrel and coronary stenting: what is the next question?

Today, following coronary stenting, clopidogrel has largely replaced ticlopidine as part of combination antiplatelet therapy following coronary stenting primarily due to its better tolerability. While there is no randomized, blinded, efficacy trial of ticlopidine versus clopidogrel, there are ample data from a number of observational studies, randomized non-blinded trials, and a randomized blinded safety trial to prove that clopidogrel is not only safer than ticlopidine, but also at least as efficacious following stenting. With over 10,000 treated patients, pooled data suggest similar rates of stent thrombosis (clopidogrel 0.98% vs. ticlopidine 0.98%) and lower rates of major adverse cardiac events with clopidogrel (clopidogrel 1.63% vs. ticlopidine 4.52%, p<0.001), with a clear advantage for clopidogrel regarding adverse events (clopidogrel 5.91% vs. ticlopidine 9.75%, p<0.001). With clopidogrel's superior safety and at least equivalent efficacy, the question of "which thienopyridine?" post-stenting has been answered. Now the questions "how much?", "how soon?" and "how long?" must be addressed. The Clopidogrel for the Reduction of Events During Observation (CREDO) trial is a multi-center, double-blind, randomized trial designed to answer these remaining questions. CREDO will evaluate the efficacy and safety of clopidogrel pretreatment versus no pretreatment, and prolonged (1 year), versus short-term (1 month) dual antiplatelet therapy in 2,000 patients undergoing planned or highly probable coronary intervention with a stent.

Glycoprotein IIb/IIIa receptor antagonists for the treatment of unstable angina.

Unstable angina and non-Q-wave myocardial infarction, part of the acute coronary syndromes, are characterized by coronary arterial plaque rupture and endovascular thrombus formation. Plaque rupture leads to exposure of subendothelial components such as collagen and fibronectin, and these substances are known to cause platelet activation, aggregation, and initiation of the coagulation cascade. Aspirin and heparin have been used as therapeutic mainstays for acute coronary syndromes, acting as antiplatelet and antithrombin agents, respectively. Despite treatment with this conventional anticoagulant strategy and antianginal drugs, substantial morbidity and mortality continue to be associated with unstable angina and non-Q-wave myocardial infarction. Specific antagonists of the platelet glycoprotein IIb/IIIa inhibitor have proved effective in substantially reducing ischemic events following percutaneous coronary revascularization, and several trials using these agents in acute coronary syndromes are now completed. Compared to patients receiving standard therapy (aspirin and heparin), platelet IIb/IIIa antagonists have further reduced the incidence of major ischemic events. Ongoing studies are addressing the optimal extent and duration of platelet inhibition in patients with acute coronary syndromes.

Antiplatelet medications and their indications in preventing and treating coronary thrombosis.

Platelets play a pivotal role in the pathophysiology of unstable angina, acute myocardial infarction, and complications following percutaneous coronary intervention. Three classes of platelet-inhibiting drugs, aspirin, thienopyridines and platelet glycoprotein IIb/ IIIa inhibitors, are now commonly used for the prevention and treatment of disorders of coronary artery thrombosis. For the last several decades aspirin has been the sole option for antiplatelet therapy in the treatment and prevention of the manifestations of cardiovascular disease. However, a wider selection of antiplatelet agents, including the thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein (GP)IIb/IIIa receptor antagonists, are now available and provide clinicians with the opportunity to potentially improve upon the previous gold standard of aspirin. This review summarizes these drugs and the scientific data that have led to their use in primary and secondary prevention, unstable angina, myocardial infarction, and percutaneous coronary intervention.

Complications of oral antiplatelet medications.

One by-product of the flurry of large-scale clinical trials accompanying the emergence of drugs that inhibit platelet function is volumes of information chronicling the adverse effects of this class of medications. One aspect all antiplatelet drugs share is a propensity toward bleeding. Beyond that similarity, however, the different pharmacologic agents in this broad collection have few attributes in common. Aspirin, by virtue of its long history, has been studied most extensively, and has proven to be an exceptionally valuable therapy. However, the complicated adverse profile of this seemingly simple drug is commonly overlooked by practitioners and deserves clinical review. The thienopyridine class (including ticlopidine and clopidogrel) share certain peculiarities that continue to be clarified, including life-threatening thrombotic thrombocytopenia purpura. Dipyridamole is a veteran drug that is enjoying renewed attention as a prophylactic aid in preventing cerebrovascular events. One class, the oral platelet glycoprotein IIb/IIIa receptor inhibitors, has failed to find its way into clinical implementation due to an unfavorable balance between efficacy and adverse effect. This review summarizes the adverse profiles of each of these drug classes and draws on data gathered in large clinical studies.

Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting.

CONTEXT: Thrombotic thrombocytopenic purpura (TTP) is a rare and often fatal disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, mental status changes, and renal dysfunction. Ticlopidine hydrochloride is 1 of several drugs that have been associated with this disorder and is currently used routinely in the approximately 500000 patients per year in the United States who undergo a percutaneous coronary intervention involving a stent. OBJECTIVES: To determine the incidence and describe the clinical course of TTP due to ticlopidine therapy following stenting. DESIGN: Retrospective analysis of cohort of all patients undergoing coronary stenting at the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) study sites. SETTING: Sixty-three centers throughout the United States and Canada. PATIENTS: A total of 43322 patients who underwent a percutaneous coronary intervention and received a coronary stent during a 1-year period from 1996 to 1997. MAIN OUTCOME MEASURES: Cases of TTP following stenting during the 1-year period to determine the incidence of TTP due to ticlopidine therapy following coronary stenting. Additional cases were collected from these and other centers across North America to further describe the clinical presentation and course of TTP due to ticlopidine therapy following stenting. RESULTS: Nine cases of TTP following stenting were recognized at the 63 centers during the specified period, giving an incidence of 1 case per 4814 patients treated (0.02%; 95% confidence interval, 1 case per 2533 to 1 case per 10 541 patients treated). Ten additional cases of TTP related to ticlopidine therapy following stenting were identified from other centers, were identified from the primary centers outside the pre-defined period, or involved a noncoronary stent. Four patients (21%) received ticlopidine for 2 weeks or fewer, 14 patients (74%) for 2 to 4 weeks, and 1 patient (5%) for 8 weeks. The mean time of ticlopidine treatment prior to TTP diagnosis was 22 days (range, 5-60 days). The overall mortality rate was 21% (4/19), with all 4 deaths occurring in patients not treated with plasmapheresis, whereas there were no deaths among the 13 patients who received plasmapheresis. CONCLUSION: The findings of a TTP incidence of 0.02% in our cohort of ticlopidine-treated patients following coronary stenting suggests that TTP occurs much more commonly in this population than the estimated incidence of 0.0004% in the general population. The mortality rate for this rare complication exceeds 20%. Limiting ticlopidine therapy to 2 weeks after stenting does not prevent the development of TTP. Rapid diagnosis and treatment that includes plasmapheresis are critical for improved survival.