A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention.

Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban.

Rationale and design of the TAXUS Liberte Post-Approval Study: examination of patients receiving the TAXUS Liberté stent with concomitant prasugrel therapy in routine interventional cardiology practice.

BACKGROUND: Observational studies of new coronary stents are necessary to assess performance in a variety of complex patient and lesion types. Furthermore, the optimal dose and duration of thienopyridine treatment is unclear, particularly in patients with complex clinical conditions. The TAXUS Liberte Post-Approval Study is designed to provide 5-year data on the TAXUS Liberté paclitaxel-eluting stent with concomitant prasugrel therapy in routine clinical practice and to contribute data to the DAPT study. STUDY DESIGN: The TAXUS Liberte Post-Approval Study is a prospective, multicenter, observational study. Enrollment of approximately 4,200 patients receiving ≥1 TAXUS Liberté stents is planned. All patients without a contraindication will be prescribed prasugrel plus aspirin for 1 year. The 12-month primary end point of cardiac death or myocardial infarction in on-label stent patients will be compared with historical TAXUS Express stent data from the TAXUS ATLAS and TAXUS ARRIVE studies. Secondary clinical end points include stent thrombosis, all-cause death, stroke, revascularization, and bleeding in all patients. In addition, this study will be the first to evaluate prasugrel use in a routine practice setting (including 5 and 10 mg daily doses) and will contribute data to the DAPT Study, comparing 12 versus 30 months of dual antiplatelet therapy after drug-eluting stent placement. SUMMARY: The TAXUS Liberte Post-Approval Study will be the first to provide long-term real-world data on use of the TAXUS Liberté Stent with prasugrel treatment. The study is currently enrolling, and primary end point data are expected in mid 2013.

Management of high blood pressure in clinical practice: perceptible qualitative differences in approaches utilized by clinicians.

The authors recruited a group of physicians from among the investigators participating in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with a greater (more successful) or lesser (less successful) proportion of trial patients meeting blood pressure (BP) control goals. The authors utilized qualitative focus group methods to identify similarities and differences in practice behaviors. Successful and less successful physicians had similarities in knowledge and practice behaviors regarding awareness of treatment guidelines, approaches to diagnosis, use of pharmacologic management, and the opinion that systolic BP guidelines should consider a patient's age. However, there were discernible differences between the two physician groups in their views on doctor-patient relationships: physicians from the less successful group were more paternalistic with their patients, while physicians from the more successful group were more likely to use a patient-centered clinical approach to BP awareness and management.

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Heart Failure Validation Study: diagnosis and prognosis.

BACKGROUND: ALLHAT, a randomized, double-blind, active-controlled hypertension treatment trial in 42,418 patients, reported that a thiazide-type diuretic (chlorthalidone) was superior to a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha1-blocker (doxazosin) in preventing the new onset of heart failure (HF). However, questions have been raised regarding the validity of the HF diagnosis. METHODS: The ALLHAT HF Validation Study was designed to validate and elucidate the significance of HF events in ALLHAT. Records for 2778 HF hospitalizations in 1935 patients were centrally reviewed using several prespecified algorithms (based on ALLHAT and Framingham criteria) and reviewers' global clinical judgment. Percent agreement with diagnoses assigned by ALLHAT site physicians, relative risks across randomized comparisons, incidence rates, and mortality after HF hospitalization were evaluated for first events validated by each of the criteria sets. RESULTS: Percent agreements with site physician diagnoses were 71%, 80%, and 84% for ALLHAT, Framingham, and reviewers' judgment, respectively. Using these 3 criteria, relative risks (95% CI) for new-onset HF compared with chlorthalidone were, respectively, 1.46 (1.27-1.68), 1.42 (1.25-1.62), and 1.45 (1.28-1.64) for amlodipine; 1.18 (1.02-1.28), 1.13 (0.99-1.30), and 1.15 (1.01-1.32) for lisinopril; and 1.79 (1.51-2.11), 1.71 (1.46-2.00), and 1.80 (1.55-2.10) for doxazosin. CONCLUSIONS: An independent review of source documentation showed a high degree of agreement with the HF diagnoses assigned by site physicians and confirmed the higher risk of HF associated with first-step therapy using amlodipine, lisinopril, or doxazosin compared with chlorthalidone. Thiazide-type diuretics should be the preferred first-step therapy for prevention of HF in high-risk patients with hypertension.

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease.

BACKGROUND: Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. METHODS: The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. RESULTS: There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. CONCLUSIONS: Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.