Background Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care.Purpose We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial – POC-CT) of a ‘learning healthcare system,’ and settles a clinical question of interest to the VA.Methods This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA’s automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently ‘winning’ strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy.Limitations Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of...

SUMMARY To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandln levels by radioimmunoassay before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained immeasurable and that of thromboxane A, did not change, while the metabolite of PGE, (PGE-M) increased by 53% (34 ± 4 pg/ml pre-captopril, 52 ± 5 pg/ral after; p < 0.001). As expected, blood pressure (BP) and angiotensin II (AH) levels fell, and kinin levels rose (all changesp < 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 ± 3 mm Hg pre-synthetase inhibition vs -13 ± 2 mm Hg post; p < 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 ± 4 mm Hg pre, -18 ± 5 mm Hg post). Neither indomethacin nor aspirin changed the AH or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state. hormones, the prostaglandins, may also be involved. It is known that bradykinin releases prostaglandins from several tissues, 1 " 7 and it has been postulated that inhibition of kininase II with CEI could increase endogenous kinin levels, permitting more kinin-mediated prostaglandin release. Murthy et al. 8 have provided indirect evidence in rabbits supporting this postulate by showing that prostaglandin synthetase inhibition partially blocks the hypotensive response to bradykinin after CEI. Vinci et al. 9 found that the peptide CEI, SQ 20,881, increased plasma immunoreactive prostaglandin E levels in some hypertensive subjects.In the studies reported here, we examined the potential importance of the prostaglandins in mediating the depressor response to the oral CEI, captopril, in hypertensive patients both by measuring the changes in plasma prostaglandin levels after CEI and by assessing the effect of prostaglandin synthetase inhibition on the response to CEI. Our results show that captopril does increase endogenous prostaglandin production and that prostaglandins contribute to captopril's antihypertensive effect.

Abstract-NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (nϭ111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (nϭ105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Key Words: hypertension, essential Ⅲ indomethacin Ⅲ losartan Ⅲ captopril Ⅲ blood pressure N onsteroidal anti-inflammatory drugs (NSAIDs) are among the most common classes of medications prescribed in the United States. The availability of over-thecounter formulations has increased their use further, particularly among the elderly. 1 Given the high prevalence of hypertension, it is likely that concomitant use of NSAIDs and antihypertensive medication will occur in the same patient.There are numerous studies and meta-analyses that have focused on the adverse effects of NSAID medications on blood pressure and the blunting of the efficacy of antihypertensive medications. Most classes of antihypertensive drugs appear to be affected; these include diuretics, 2 ␤-blockers, 2,3 and angiotensin-converting enzyme inhibitors (ACEIs). 4 -7 The most widely studied of the NSAID medications is indomethacin, which has been shown to increase mean blood pressure by as much as 5 mm Hg in treated hypertensive patients. 8 The clinical relevance of these blood pressure changes can be tied to the observation that NSAID use in the elderly is associated with an increased likelihood of the subsequent initiation of antihypertensive therapy. 9 In part, the increase in blood pressure resulting from NSAID administration may be nonspecific (ie, related to fluid retention), and these effects may affect antihypertensive medications equally. However, given the inhibition of prostaglandin synthesis by NSAIDs, there is reason to believe that ACEIs may be particularly affected. ACEIs prevent the breakdown of bradykinin, which has been shown to increase prostaglandin synthesis. 10 Not unexpectedly, concomitant administration of indomethacin in captopril-treated patients reversed 40% of the antihypertensive effect in hypertensive patients 4,5 and attenuated the favorable hemodynamic effects in patients with congestive heart failure. 7 The new class of antihypertensive agents, angiotensin II receptor antagonists, directly opposes the interaction of angiotensin II with its cell surface receptor. Angiotensin II receptor antagonists reduce blood pressure to a degree similar to that for most other classes of antihypertensive medications. However, in contrast to ACEI, there is ...

A B S T R A C T Captopril is a potent hypotensive agent whose efficacy has hitherto been attributed to its ability to alter either angiotensin II formation or kinin degradation. Our purpose was to examine captopril's acute effect on prostaglandin production, because changes in neither the renin-angiotensin nor the kallikrein-kinin systems appear adequate to account for the fall in arterial pressure. The plasma levels of' angiotensin II, kinins, and prostaglandins were determined in response to increasing doses (5, 12.5, and 25 mg) of captopril and these responses were compared with the change in arterial pressure observed in nine supine normal male subjects studied on both a high (200 meq) and low (10 meq) sodium intake.Captopril significantly (P < 0.01) increased the levels of the 13,14-dihydro-15-keto metabolite of prostaglandin E2 (PGE2-M), a potent vasodilator, with similar responses being observed on both a high aind a low sodium intake. No significant changes in the plasma levels of 6-keto-prostaglandin F,a, or thromboxane B2, the stable products of prostacyclin and thromboxane A2, respectively, occurred.The depressor response to captopril correlated with the change in PGE2-M (r = 0.52, t = 5.44, P < 0.0001). On the other hand, although significant (P < 0.02) decrements in angiotensin II and increments in plasma kinins accompanied the hypotensive response in sodium-restricted subjects, in sodium-loaded subjects where the renin-angiotensin system was suppressed, nio change in angiotensin II, and only a modest change in kinins was noted, even though significant (P < 0.01) decrements in diastolic blood pressure occurred (-10+2 mm Hg).Thus, changes in depressor prostaglandin production can better account for the hypotensive response to