Coronary Artery Drug-eluting Stents Research Articles

After placement of a newer-generation drug-eluting coronary artery stent in a patient with a high bleeding risk, does one month of dual antiplatelet therapy effectively reduce the incidence of major bleeding while also maintaining stent effectiveness?

After placement of a newer-generation drug-eluting coronary artery stent in a patient with a high bleeding risk, does one month of dual antiplatelet therapy effectively reduce the incidence of major bleeding while also maintaining stent effectiveness?

Early Discontinuation of Aspirin Among Patients with Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention with a Drug-Eluting Stent: A Meta-Analysis.

Conflicting evidence exists to support whether short duration of dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy reduces bleeding complications after coronary artery drug-eluting stent (DES) insertion, compared with standard 12-month DAPT, particularly among patients with CKD who are at increased risk of bleeding. A Medline search identified randomized trials comparing up to 3 months of DAPT followed by P2Y12 inhibitor monotherapy versus twelve months of DAPT after insertion of a DES for any indication. Trials were included if they reported ischemic or bleeding outcomes among patients with CKD. The primary outcome was a composite of all-cause mortality, cardiac or cerebrovascular events, stent thrombosis (MACE), and major or minor bleeding events. Secondary outcomes were the individual components of the primary outcome, and clinically significant bleeding. The relative risk (RR) was estimated using a random-effects model. Seven randomized trials were included for a total of 4,996 patients with CKD (14% of the trial population). Early discontinuation of aspirin was associated with a similar incidence of the primary outcome among patients with CKD compared with twelve-month DAPT (RR 0.97; 95% confidence interval (95% CI) 0.73-1.30). The relative risk of MACE was also similar between the two arms (RR 1.02; 95% CI 0.85-1.23). The risk of clinically significant bleeding was significantly lower with early discontinuation of aspirin (RR 0.60; 95% CI 0.46-0.78). P2Y12 inhibitor monotherapy after a shortened course of DAPT appears to be associated with a similar risk of ischemic events and a lower risk of bleeding events after DES insertion among patients with CKD compared to 12-month DAPT.

Amphiphilic Core Cross-Linked Star Polymers for the Delivery of Hydrophilic Drugs from Hydrophobic Matrices.

The delivery of hydrophilic drugs from hydrophobic polymers is a long-standing challenge in the biomaterials field due to the limited solubility of the therapeutic agent within the polymer matrix. In this work, we develop a drug delivery mechanism that enables the impregnation and subsequent elution of hydrophilic drugs from a hydrophobic polymer material. This was achieved by synthesizing core cross-linked star polymer amphiphiles with hydrophilic cores and hydrophobic coronas. While significant work has been done to create nanocarriers for hydrophilic drugs, this work is distinct from previous work in that it designs amphiphilic and core cross-linked particles for controlled release from hydrophobic matrices. Ultraviolet-mediated atom transfer radical polymerization was used to synthesize the poly(ethylene glycol) (PEG)-based hydrophilic cores of the star polymers, and hydrophobic coronas of poly(caprolactone) (PCL) were then built onto the stars using ring-opening polymerization. We illustrated the cytocompatibility of PCL loaded with these star polymers through human endothelial cell adhesion and proliferation for up to 7 days, with star loadings of up to 40 wt %. We demonstrated successful loading of the hydrophilic drug heparin into the star polymer core, achieving a loading efficiency and content of 50 and 5%, respectively. Finally, the heparin-loaded star polymers were incorporated into a PCL matrix and sustained release of heparin was illustrated for over 40 days. These results support the use of core cross-linked star polymer amphiphiles for the delivery of hydrophilic drugs from hydrophobic polymer matrices. These materials were developed for application as drug-eluting and biodegradable coronary artery stents, but this flexible drug delivery platform could have impact in a broad range of medical applications.

Progress on developing an effective below-the-knee drug-coated balloon.

Infrapopliteal atherosclerotic disease continues to present the greatest conundrum for effective endovascular therapies. To date, conventional angioplasty has been fraught with early restenosis and recoil in these complex, long, calcified, and occlusive lesions. The success of metallic drug-eluting stents in coronary arteries has not carried over to below-the-knee arteries. Initial promise in paclitaxel-coated balloons has not been demonstrated in large randomized clinical trials. Furthermore, the potential association between paclitaxel and mortality continues to generate tremendous controversy. The goal of this review article is to discuss the evolution and challenges of drug-coated balloon (DCB) science, present the clinical results of currently available tibial DCBs, and introduce new horizons in DCB technology.

Abstract 15121: Mortality in Cancer Patients Undergoing Percutaneous Coronary Intervention: Insights From a Hospital-based Cross-sectional Study

Introduction: Comorbid risk factors between cancer and coronary artery diseases (CAD) and underlying pathogenesis of inflammation and oxidative stress led to an increase in the number of cancer patients developing CAD. Hypothesis: The prime purpose of our hospital-based study is to evaluate the risk of mortality due to cancer and chronic comorbidities in post-percutaneous coronary intervention (PCI) patients. Methods: We conducted a cross-sectional study using the nationwide inpatient sample (NIS, 2012 to 2014) including 1,131,415 adult patients undergoing PCI with placement of non-drug and/or drug-eluting coronary artery stents. The logistic regression model was used to assess the odds ratio (OR) of the association between comorbid cancer and mortality in post-PCI hospitalized patients. Results: Most of the post-PCI patients with cancer were older adults (mean age 70.6 years), males (71.8%), and Caucasians (80.6%). Females (OR 1.28, 95% CI 1.24-1.34) had higher odds of post-PCI mortality risk compared to males. Among all comorbidities, coagulopathy and deficiency anemia were associated with increased risk of mortality by three times (95% CI 2.837-3.250) and 1.6 times (95% CI 1.534-1.692), respectively in post-PCI hospitalized patients. Comorbid cancer was associated with an increased risk of mortality in post-PCI hospitalized patients (OR 1.88, 95% CI 1.69-2.09) after controlling for potential confounders. Conclusions: Cancer is a significant risk factor increasing the risk of mortality by 88% in post-PCI hospitalized patients. An integrated care model requiring more vigilance and aggressive management for the complex patient population with cancer and other comorbidities are needed.

P6138Quality of clinical trial evidence on devices and drugs approved to treat coronary artery disease

Abstract Background Regulatory approval of drugs and devices follow two different pathways. Whether different approval pathways underlie meaningful differences in quality of clinical trial evidence is unknown. We aimed to compare the quality of evidence of clinical trials that served as a basis for approval by the U.S. Food and Drug Administration (FDA) of drugs and devices used for the treatment of coronary artery disease. Methods FDA databases were searched for devices (i.e., coronary artery drug-eluting stents) and drugs (i.e., agents targeting atherothrombosis) approved between January 1st, 2001 and December 31st, 2017. FDA medical reviews were screened to identify trials that served for approval purposes. The pre-specified primary outcome was the prevalence of randomized trials used for approval (i.e. number of randomized trials/overall number of trials). Results A total of 97 trials were identified, 39 serving for approval of 13 devices and 58 serving for approval of 8 drugs. Devices were evaluated by fewer trials per item as compared with drugs (3.0±1.4 vs. 7.3±5.3, P=0.012) with similar study size (501 [100–1314] vs. 379 [183–904] patients per trial, P=0.55). Trials evaluating devices were less frequently randomized (56.4% vs. 94.8%, P<0.001) and more frequently designed powered for clinical endpoints (53.8% vs. 17.2%, P<0.001) as compared to those evaluating drugs. Use of randomization declined over time among trials supporting FDA approval of devices. In addition, significant differences were present between trials evaluating devices and those evaluating drugs in terms of study design, comparator used, blinding to treatment allocation, primary hypothesis, primary endpoint, and type of patients included. Use of randomized trials for approval Conclusions There are substantial differences in clinical trial evidence serving for FDA approval of devices and drugs used for treatment of coronary artery disease. The lower degree of randomized evidence used for approval of devices as compared to drugs raises some concerns, particularly in view of its decline over time.

Device specificity of vascular healing following implantation of bioresorbable vascular scaffolds and bioabsorbable polymer metallic drug-eluting stents in human coronary arteries: the ESTROFA OCT BVS vs. BP-DES study

We sought to compare vascular healing with bioresorbable everolimus-eluting vascular scaffolds (BVS) and drug-eluting stents with bioabsorbable polymers (BP-DES) at six and 12 months both implanted in the same patients. This was a multicentre and prospective study including patients with at least two comparable lesions to treat. In every patient both BVS and BP-DES (SYNERGY, Orsiro or BioMatrix Flex) were implanted by lesion randomisation. Patients included were evaluated with optical coherence tomography at six or 12 months (2:1). Finally, 68 patients had an examination at six months and 27 patients at 12 months. The rates of uncovered struts at six months were 1.7±3.2% for BVS and 5.3±5.6% for BP-DES (p=0.0001), and at 12 months 0.48±0.72% and 4.8±5%, respectively (p=0.001). Rates of strut malapposition were significantly lower with BVS. There was no significant intra-patient correlation with BP-DES/BVS for endpoints. Evaginations were more frequent and larger with BVS. Discontinuities in BVS were observed in 19.4% at six months and 14.3% at 12 months. Vascular healing with BVS and BP-DES could be more device-specific than patient-specific. At follow-up, BVS presented fewer uncovered or non-apposed struts than BP-DES but more frequent and larger evaginations. Discontinuities in BVS were relatively frequent at both time points.

Uptake of medical devices approved by NICE

BackgroundThe UK is sometimes considered to be slow in adopting new technologies. The recent Accelerated Access Review examined adoption challenges and identified opportunities for improvements. This study aims to determine...

Formation of microcapsules by ultrasound stimulation for use in remote-controlled drug-eluting stents

Coronary Heart Disease (CHD) is the leading cause of death globally. The placement of drug-eluting stents (DESs) in diseased coronary arteries is the most successful minimally-invasive intervention to treat CHD. The key limitations of such interventional therapy are the risk of in-stent restenosis (ISR) and late stent thrombosis. This paper investigates a new drug-release system by formatting nanoparticles as drug carriers, which are later subjected to an external ultrasonic stimulus for controlled drug release remotely for DESs. The drug delivery could delay smooth muscle cell growth whilst enabling effective regeneration of a functional endothelium. Microcapsules were produced by employing a layer-by-layer technique, encapsulated with Rhodamine 6G dye used in place of anti-restenotic drugs. Gold nanoparticles were employed as a shell in the microcapsules. The presence of gold nanoparticles significantly enhanced the efficiency of the ultrasonically induced dye release from the microcapsules and increased the sensitivity of the microcapsules to ultrasonic stimulation compared to those without gold nanoparticles.

TCTAP A-106 Ultra-long Coronary Artery Drug Eluting Stents: Outcome from Real World Tertiary Centre Experience

PCI of long diffuse coronary lesions are often challenging. Data regarding usage and real-world outcomes of very long coronary stents are limited. This retrospective study sought to determine the safety, the efficacy of the procedure and 1-year outcome in terms of MACE in patients treated with Ultra

Polymer-Free Versus Biodegradable Polymer Drug-Eluting Coronary Artery Stents: A Meta-Analysis of Randomised Trials Including 1,975 Patients

Polymer-Free Versus Biodegradable Polymer Drug-Eluting Coronary Artery Stents: A Meta-Analysis of Randomised Trials Including 1,975 Patients

Long- vs. Short-Term Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation

Guidelines recommend dual antiplatelet therapy (DAPT) for a minimum of 6 months following drug-eluting coronary artery stent implantation (NEJM JW

PB-08Damage to Polymer of Coronary Artery Drug Eluting Stents during Percutaneous Coronary Intervention

PB-08Damage to Polymer of Coronary Artery Drug Eluting Stents during Percutaneous Coronary Intervention

Changes in Drug Eluting Stent Usage During a Four-Year Time Period in a Regional Cath Lab in New South Wales

The safety and cost effectiveness of Drug eluting stents (DES) were not well established compared to Bare metal stents (BMS) in the past1. Earlier guidelines had recommended a selective use of DES2,3. However, subsequent studies have shown that DES, particularly the newer generation stents have better safety profile than BMS4. The aim of this analysis was to study the changes in DES usage in a regional Cath Lab at Lismore Base Hospital in NSW during a four year time period from 2012 to 2015. A total of 515 cases of coronary angioplasty with stenting were done during this period (average age 67+/-12 years; 67% males). 666 stents were used. Average number of stents used per case was 1.3. In 2012 out of the 146 stents used for 112 cases, 90 were DES (62%) and 56 were BMS (38%). The number of DES used was 116(70%) and BMS was 50(30%) out of a total 166 stents used for 125 cases in 2013. In 2014 the number of DES used was 123(64%) and BMS was 68(36%) out of total 191 stents for 146 cases. In 2015 the DES usage was 146(90%) and BMS usage was 17(10%) out of 163 stents used in 132 cases. The current study showed a clear increase in DES usage from an average 65% between 2012 and 2014 to 90% in 2015. This reflects the current recommendations for use of new generation DES, which have improved safety profile, clinical efficacy and cost effectiveness compared to BMS4,5.1.Lagerqvist B, James SK, Stenestrand U, Lindback J, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356(10):1009-1019.2.King SB 3rd, Smith SC Jr, Hirshfeld JW Jr et al., 2007 focussed update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol. 2008 Jan 15;51(2):172-209.3.Clinical Guidelines for the Use of Drug Eluting Coronary Artery Stents in Public Hospitals in NSW. Greater Metropolitan Clinical Taskforce Cardiac Coordinating Committee, May 2008.4.Windecker S, Kolh P, Alfonso F et al., 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2014 Oct 1;35(37):2541-2619..5.Revision of clinical guidelines for the use of Drug eluting coronary artery stents in public hospitals in NSW. Agency for clinical innovation draft publication 2015.

Improved outcomes of elderly patients treated with drug-eluting versus bare metal stents in large coronary arteries: Results from the BAsel Stent Kosten-Effektivitäts Trial PROspective Validation Examination randomized trial

Drug-eluting stents (DES) improve outcomes in elderly patients with small coronary artery disease compared with bare-metal stents (BMS), but randomized data in elderly patients in need of large coronary stents are not available. Planned secondary analysis of patients ≥75 years recruited to the "BASKET-PROVE" trial, in which 2,314 patients undergoing percutaneous coronary intervention for large (≥3.0 mm) native vessel disease were randomized 2:1 to DES (everolimus- vs sirolimus-eluting stents 1:1) versus BMS. All patients received 12 months of dual antiplatelet therapy. The primary end point was a composite of cardiac death or nonfatal myocardial infarction at 2 years. Comparison of DES versus BMS among 405 patients ≥75 years showed significantly lower rates of the primary end point for DES (5.0% vs 11.6%; hazard ration (HR) 0.64 [0.44-0.91]; P = .014). Rates of nonfatal myocardial infarction (1.2% vs 5.5%, hazard ration (HR) 0.44 [0.21-0.83]; P = .009), all-cause death (7.4% vs 14.4%; HR 0.7 [0.51-0.95]; P = .02), and target vessel revascularization (TVR) (2.3% vs 6.2%; HR 0.59 [0.34-0.99]; P = .046) were also lower, whereas stent thrombosis and bleeding rates were similar. In contrast, among patients <75 years (n = 1,909), the only significant benefit of DES was a reduced rate of TVR (4.0% vs 8.7%, HR 0.66 [0.55-0.80]; P < .0001). In patients ≥75 years requiring large (≥3.0 mm) coronary stents, use of DES was beneficial compared with BMS and reduced the rate of ischemic events, mortality, and TVR. These data suggest that DES should be preferred over BMS in elderly patients.

Abstract 711: In Hospital Complications After PCI After Insertion of DES versus BMS in the United States

Background: We evaluated the potential differences in patient complications and in-hospital mortality for patients who underwent primary percutaneous coronary intervention (PCI) with insertion of drug-eluting coronary artery stent (DES) versus those with insertion of bare metal stent (BMS) in the United States. Method: We used the Nationwide Inpatient Sample to examine differences in all-cause in-hospital mortality between DES versus BMS patients with a principal diagnosis of STEMI, NSTEMI and Coronary atherosclerosis ICD-9 codes. Bivariate and adjusted logistic regression analysis were used to identify any associations with DES versus BMS with increased subsequent complications and in-hospital mortality. Results: We identified 9140 admissions with PCI as a primary intervention, of which 85.03% native coronary artery stenosis, 5.9% presented with NSTEMI, 4.9% had STEMI, and 4.0% revascularized due to graft stenosis. Patients with graft stenosis and STEMI had the highest rates of BMS insertion (62% and 49% respectively). The odds of in-hospital mortality were higher for BMS insertion among all for different group. However, the association lost the statistical significance after adjusting for patient characteristics, except for patients with native coronary artery stenosis (OR =1.96 95% CI: 1.02-3.8). Major complications, including vascular, neurological, and mechanical complications were higher for BMS insertion for NSTEMI and graft coronary atherosclerosis patients. However, BMS insertion associated with less complication in STEMI patients and native coronary atherosclerosis. the later didn’t reach the statistical significance level. Interestingly, there was no in-hospital mortality in our sample among male with DES insertion. Conclusion: The clinical context of PCI and choice of DES versus BMS, with BMS a preferential choice in patients with evidence of thrombus (STEMI) is reflected in downstream complications and in-hospital mortality.

Impact on In-Hospital Outcomes With Drug-Eluting Stents Versus Bare-Metal Stents (from 665,804 Procedures)

Contemporary large-scale data, regarding in-hospital outcomes depending on the types of stent used for percutaneous coronary intervention (PCI) is lacking. We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample from 2006 to 2011 using the International Classification of Diseases, Ninth Revision, Clinical Modification procedure code 36.06 (bare-metal coronary artery stent, BMS) or 36.07 (drug-eluting coronary artery stent, DES) for PCI. All analyses were performed using the designated weighting specified to the Nationwide Inpatient Sample database to minimize bias. Primary outcome was in-hospital mortality. Wald's chi-square test was used for categorical variables. We built a hierarchical 2 level model adjusted for multiple confounding factors, with hospital identification incorporated as random effects in the model and propensity match analyses were used to adjust confounding variables. A total of 665,804 procedures were analyzed, which were representative of 3,277,884 procedures in the United States. Use of bare-metal stents (BMS) was associated with greater occurrence of in-hospital mortality compared with that of drug-eluting stents (DES; 1.4% vs 0.5%, p <0.001). The association stayed significant after adjustment of various possible confounding factors (odds ratio for DES versus BMS 0.59 [0.54 to 0.64, p <0.001]) and also in propensity matched cohorts (1.2% vs 0.7%, p <0.001). The results continued to be similar in the following high-risk subgroups: diabetes (0.57 [0.50 to 0.64, <0.001]), acute myocardial infarction and/or shock (0.53 [0.49 to 0.57, <0.001]), age >80 (0.66 [0.58 to 0.74, <0.001]), and multivessel PCI (0.55 [0.46 to 0.66, <0.001]). In conclusion, DES use was associated with lesser in-hospital mortality compared with BMS. This outcome benefit was seen across subgroups in various subgroups including elderly, diabetics, and acute myocardial infarction as well as multivessel interventions.

Clopidogrel Use and Early Outcomes Among Older Patients Receiving a Drug-Eluting Coronary Artery Stent

Clopidogrel use after drug-eluting stent (DES) coronary artery implantation is essential for the prevention of early in-stent thrombosis, but clopidogrel use among older DES recipients has not been widely studied. We sought to identify characteristics associated with failure to fill a clopidogrel prescription and to examine the relationship between a clopidogrel prescription fill and hospitalization for acute myocardial infarction (AMI) or death. This study was a retrospective analysis of administrative data (20% sample) of 15 996 Medicare Part D enrollees who received a DES in 2006 to 2007. We modeled the adjusted probability and odds of clopidogrel prescription fill within 7 and 90 days of discharge and its association with AMI hospitalization or death. Of the study sample, 19.7% did not fill a clopidogrel prescription within 7 days of discharge, falling to 13.3% by day 90. The adjusted probability of filling a clopidogrel prescription within 7 or 90 days of discharge was lower for patients with dementia (20.2% less likely; 95% CI, 10.4%-30.1%), depression (10.7% less likely; 95% CI, 6.9%-14.5%), age >84 years compared to age 65 to 69 years (10.6% less likely; 95% CI, 8.6%-12.7%), black race (6.6% less likely; 95% CI, 4.2%-9.0%), intermediate levels of medication cost share (5.2% less likely; 95% CI, 2.9%-7.6%), and female sex (3.3% less likely; 95% CI, 2.1%-4.5%). It was higher for patients initially hospitalized for an AMI (12.5% more likely; 95% CI, 11.3%-13.6%). Failure to fill a clopidogrel prescription within 7 days of discharge was associated with a higher adjusted odds ratio of death during days 8 to 90 (2.44; 95% CI, 1.76-3.38) but was not associated with an increased risk of hospitalization for AMI. One in 5 patients failed to fill a prescription for clopidogrel at 7 days after DES placement, and 1 in 7 failed to do so by 3 months. Individual characteristics available at the time of hospital discharge were associated with a clopidogrel prescription fill. Those characteristics most strongly associated with nonadherence, including age >84 years, not having an AMI, depression, and dementia, may guide clinicians and health systems seeking to target this high-risk population and improve health outcomes after percutaneous coronary intervention.

Residual Platelet Reactivity, Bleedings, and Adherence to Treatment in Patients Having Coronary Stent Implantation Treated With Prasugrel

Recent guidelines have recommended the use of aspirin and prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention. However, prasugrel use has been evaluated only in randomized trials. This study sought to evaluate bleeding rates and adherence to treatment in "real-world" patients treated with prasugrel. In total 298 consecutive patients 68 ± 10 years old (31% >75 years old) underwent stent implantation and received prasugrel therapy. Indications to prasugrel therapy were (1) ST-elevation acute myocardial infarction (41%), (2) drug-eluting stent implantation in diabetics (24%), (3) stent thrombosis (3%), (4) left main coronary artery drug-eluting stent implantation (6%), and (5) percutaneous coronary intervention in patients with high residual platelet reactivity on clopidogrel therapy (26%). All patients received a loading of prasugrel 60 mg. Patients ≥75 years old and with body weight ≤60 kg received a maintenance dose of 5 mg/day (10 mg/day for all the other patients). Follow-up data including adherence to prasugrel therapy were collected by telephone interviews or outpatient visits. Minimal follow-up length was 6 months (mean 9 ± 3). Major, minor, and minimal bleedings (Thrombolysis In Myocardial Infarction criteria) occurred in 2.7%, 4.7%, and 15.1% of enrolled patients. Low residual platelet reactivity (p = 0.001) and female gender (p = 0.29) were independent predictors of bleeding events. The most frequent minimal bleeding event was epistaxis. Only 8 patients (2.7%) permanently discontinued prasugrel therapy because of bleeding events (n = 4), possible side effects (n = 2), or medical decisions not associated with bleeding or side effects (n = 2). Fourteen patients (4.7%) temporarily discontinued prasugrel (average 6.5 days) mainly because of surgical procedures. No definite or probable stent thrombosis occurred, although 3 patients develop de novo myocardial infarction and 1 an ischemic stroke. There were 11 deaths because of heart failure or refractory cardiogenic shock in 9, pulmonary embolism in 1, and cancer in 1. In conclusion, in clinical practice, major and minor bleeding event rates associated with prasugrel therapy are comparable to those reported in controlled randomized trials. The minimal bleeding event rate is higher than reported but does not seem to affect adherence to treatment.

CME Activities–Exams 1 and 2

Acute Upper Gastrointestinal Hemorrhage in an Elderly Woman Taking Aspirin and ClopidogrelClinical Gastroenterology and HepatologyVol. 9Issue 8PreviewA 72-year-old woman presents to the emergency room after 2 episodes of coffee-ground emesis and a 1-day history of melena. She has no other gastrointestinal (GI) symptoms. She complains of dizziness when standing, but denies shortness of breath and chest pain. She has a history of hypertension, diabetes, and coronary artery disease. Three weeks ago, she sustained a myocardial infarction and had 3 drug-eluting coronary artery stents placed. She takes insulin, metformin, metoprolol, aspirin, and clopidogrel. Full-Text PDF