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Objective VOLUME is a randomized, open-label, post-approval pragmatic trial aiming to evaluate long-term pulmonary and cardiovascular safety of Exubera® (EXU; insulin human [rDNA origin] Inhalation Powder) in routine clinical practice. The primary study objective is to compare risk of persistent decline in forced expiratory volume in 1 second (FEV1) among patients treated with and without EXU. Research design and methods Patients eligible to take EXU per approved local label were randomized to EXU or routine care and followed per usual care, with scheduled FEV1 tests at baseline, 6 months, and yearly. Randomization halted in October 2007 after Pfizer announced it would stop marketing EXU due to low sales. EXU patients were subsequently transitioned to usual care and all patients were followed for 6 additional months. Results Although there was insufficient power to evaluate the primary endpoint (37% of the planned 5,300 were randomized), the study provided important descriptive information. Per the primary endpoint definition, more EXU group patients (n = 8) experienced a persistent decline in FEV1 (n = 0 in usual care). Using a broader, clinically relevant pre-specified supplementary definition of persistent decline, similar numbers were observed in the EXU (n = 27) and usual care (n = 24) groups. Slightly more pulmonary and allergic serious adverse event composite endpoints were seen in the EXU group. There were no consistent treatment group differences in the cardiovascular composite endpoint, all-cause mortality, or glycemic control. Conclusions Clinically important declines in lung function that persisted more than 60 days were uncommon and of similar frequency in Exubera and usual care. Clinicaltrials.gov NCT00359801.

OBJECTIVEThe Follow-Up Study of patients previously enrolled in Exubera controlled clinical trials (FUSE) was designed to evaluate whether patients previously treated with Exubera (EXU; insulin human [rDNA origin], inhaled powder) in controlled clinical trials died because of incident primary lung cancer at a substantially higher rate than patients treated with a comparator.RESEARCH DESIGN AND METHODSFUSE is a hybrid, randomized, controlled trial/cohort study including participants of 17 prior EXU clinical trials. Pooled patient data from these trials were used, and the subset of patients enrolled in the follow-up cohort study was followed prospectively for 2 years in order to evaluate the incidence of fatal and nonfatal primary lung cancers and all-cause mortality.RESULTSThere were 24,409 person-years (PY) of observation among 7,439 trial patients, with 4,017 PY (16.5%) from the period after the trials but before the prospective follow-up and 5,299 PY (21.7%) from the prospective follow-up. Just over half of the 2,631 patients (51.6%) in the prospective follow-up were randomized to EXU in the original trial. The incidence density ratio was 2.8 (95% CI 0.5, 28.5) for lung cancer–related mortality and 3.7 (95% CI 1.0, 20.7) for incident primary lung cancer. The hazard ratio for all-cause mortality was 0.81 (95% CI 0.60, 1.10).CONCLUSIONSThese data cannot exclude an increased risk of lung cancer–related mortality associated with EXU use. If real, the absolute increased risk of lung cancer–related mortality was small (0.48 cases per 1,000 PY). For all-cause mortality—the most reliably measured end point with the clearest interpretation—EXU users did not experience an excess all-cause death rate (relative or absolute) compared with users of other diabetes treatments over the study period.

Introduction: Many clinical trials terminate early due to safety and efficacy concerns, and less often due to unexpected “positive” findings. However, early termination of post-approval (Phase IV) pragmatic randomized trials for commercial reasons is less frequent, may be more complex, and may require added flexibility in closure methods, including short term follow-up. VOLUME was a randomized, open-label, post-approval pragmatic clinical trial (PCT) or large simple trial that terminated early due to product withdrawal. The aim of this paper is to describe circumstances unique to post-approval PCTs that may require a closure amendment rather than immediate study termination, and our recommendations for operational study closure in these circumstances. We use the VOLUME case study throughout to provide a practical example. Methods: Study closeout considerations at the study level include: notifying external governance bodies, e.g., data monitoring committees (DMC), and scientific steering committees (SSC); executing a study closure amendment; notifying and training of study physicians; and institutional review board (IRB)/ethics committee (EC) approvals. Study closure considerations at the patient level focus on patient safety and include: patient notification, efficient transition to alternative treatments, the need for re-consenting; and drug supply shortages. Conclusions: Early study closeout logistics require careful analysis, detailed planning, and close coordination, and are ideally considered at the study planning phase. Lessons learned from the VOLUME closeout should help other researchers devise contingencies when terminating post approval pragmatic trials that utilize a marketed product.ClinicalTrials.gov: NCT00359801. Keywords: Large simple trial, Closure, Product withdrawal, Commercial withdrawal, Pragmatic

Aims Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines.Methods and results The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development.Conclusions A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

Nitric oxide (NO) induces the formation of intracellular cyclic guanosine monophosphate (cGMP) by guanylate cyclase. Sildenafil, which selectively inhibits phosphodiesterase type 5 (PDE5) found predominantly in the corpora cavernosa of the penis, effectively blocks the degradation of cGMP and enhances erectile function in men with erectile dysfunction. The NO-cGMP pathway also plays an important role in mediating blood pressure. It is, therefore, possible that the therapeutic doses of sildenafil used to treat erectile dysfunction may have clinically significant effects on human hemodynamics. Three studies were undertaken to assess the effects of intravenously, intra-arterially, and orally administered doses of sildenafil on blood pressure, heart rate, cardiac output, and forearm blood flow and venous compliance in healthy men. A fourth study evaluated the hemodynamic effects of intravenous sildenafil in men with stable ischemic heart disease. In healthy men, significant (p0.01) decreases in supine systolic and diastolic blood pressures were observed with intravenous sildenafil (20, 40, and 80 mg) at the end of the infusion period when plasma levels of sildenafil were highest (mean decreases from baseline of 7.0/6.9 and 9.2/6.7 mm Hg, for the 40- and 80-mg doses, respectively). These changes were transient and not dose related. Modest reductions in systemic vascular resistance also were observed (maximum decrease 16%), although heart rate was not affected by sildenafil administration when compared with placebo. Single oral doses of sildenafil (100, 150, and 200 mg) produced no significant changes in cardiac index from 1-12 hours postdose between placebo- and sildenafil-treated subjects. The approved dosage strengths of sildenafil citrate are 25 mg, 50 mg, and 100 mg. The 80-mg intravenous dose and the 200-mg oral dose of sildenafil produced comparable plasma levels at twice the maximum therapeutic dose (recommended range, 25-100 mg). After brachial artery infusion of sildenafil (up to 300 microg/min), there was a modest vasodilation of resistance arteries and a reversal of norepinephrine-induced preconstriction of forearm veins. These hemodynamic effects were similar to but smaller in magnitude than those of nitrates. In a small pilot study of men with ischemic heart disease, decreases from baseline in pulmonary arterial pressure (-27% at rest and -19% during exercise) and cardiac output (-7% at rest and -11% during exercise) were observed after 40-mg intravenous doses of sildenafil. Sildenafil was well tolerated by subjects and patients in all studies, with headache and other symptoms of vasodilation the most commonly reported adverse effects of treatment. Modest, transient hemodynamic changes were observed in healthy men after single intravenous or oral doses of sildenafil even at supratherapeutic doses. In men with stable ischemic heart disease, sildenafil produced modest effects on hemodynamic parameters at rest and during exercise.

currently account for over 10% of total healthcare expenditure across Europe and cause significant lost productivity through work

Objectives.Our primary objective was to compare the effects of three different doses of candoxatrilat with the effects of placebo on urinary volume in patients with moderately severe heart failure. The effects of candoxatrilat on urinary composition, neuroendocrine indexes and renal hemodynamic function were also studied.Background.Candoxatrilat, a neutral endopeptidase inhibitor, reduces degradation of atrial natriuretic peptide and provokes diuresis in patients with mild heart failure, but the renal effects have not been studied in patients with moderately severe heart failure in a placebo-controlled study.Methods.In a double-blind crossover trial, the effects of intravenous boluses of saline vehicle (placebo) and 50, 100 and 200 mg of candoxatrilat were compared on separate days in 12 patients with heart failure. Urinary output and composition were measured for 8 h. Renal blood flow and glomerular filtration rate were determined by radionuclide techniques. Blood was withdrawn for the measurement of hormones before and 3 h after dosing.Results.All doses of candoxatrilat increased urinary volume (e.g., [mean ± SEM] 263 ± 53 to 490 ± 82 ml for saline solution and the 200-mg dose, respectively, p < 0.01) and sodium content (14 ± 4 to 37 ± 11 mmol, p < 0.001) in the 1st 4 h after dosing. Plasma atrial natriuretic peptide increased (140 ± 26 to 279 ± 37 pg/ml, p < 0.01), whereas aldosterone decreased (178 ± 41 to 125 ± 35 pg/ml, p < 0.01), and renin activity was unchanged (10 ± 2 to 12 ± 3 ng/ml per h).Conclusions.Candoxatrilat given acutely causes diuresis, even in patients with moderately severe heart failure.

The extent to which posture altered the haemodynamic response to slow calcium channel blocker nicardipine was evaluated in 22 male patients with angiographically confirmed coronary artery disease. Patients were randomly allocated to supine or upright posture and an otherwise identical protocol performed in each group. At rest, following a control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0, and 10.0 mg) were administered by i.v. infusion over a total period of 40 min; haemodynamic indices were recorded during the 3-5 min following each 5 min infusion. The exercise effects of the drug, in each posture, were determined by comparison of a control predrug exercise with observations at the same workload following the maximal cumulative dose. Nicardipine reduced resting mean blood pressure (MBP) and systemic vascular resistance index (SVRI) in both postures, the decrease being more pronounced when upright (MBP, -12%, -18%; p less than 0.01: SVRI, -30%, -46%; p less than 0.01). The increases in cardiac index (CI) and stroke volume index (SVI) were higher when upright (29 and 54% vs. 10 and 27%; p less than 0.01). Pulmonary artery occluded pressure (PAOP) increased by 29% when upright, without change when supine. On exercise, the effects for HR, MBP, CI, SI, and SVRI responses were independent of posture; however, a qualitative difference was apparent for PAOP (-17% vs. +14%; p less than 0.05). Thus, although the actions of nicardipine were qualitatively similar, quantitative differences related to posture were confirmed. These differences appeared to relate to posture-related baseline haemodynamic differences between the groups but with similar postnicardipine absolute values.

Summary: A placebo-controlled, double-blind, dose-response study of amlodipine (1.25, 2.5, 5, and 10 mg once daily) was carried out in 136 patients with stable exertional angina pectoris. Improvements in total exercise tolerance, time to onset of angina during exercise, ST-segment deviation at maximum common load, frequency of angina attacks, and nitroglycerin consumption were greater following amlodipine than placebo. The maximum improvement in exercise parameters occurred with the highest dose of amlodipine. All doses produced significant reductions in angina attack frequency and the rate of nitroglycerin consumption. Amlodipine was well tolerated and no patients were withdrawn due to adverse events or laboratory abnormalities.

Hemodynamic dose-response effects of intravenous amrinone were studied in 22 male patients aged 38 to 62 years with left ventricular failure occurring within 18 hours of acute myocardial infarction. After hemodynamic confirmation of a raised left-sided cardiac filling pressure--pulmonary artery occluded pressure greater than 20 mm Hg--patients were randomized to either low-dose infusion of amrinone (200 micrograms/kg/hr for 30 minutes, 400 micrograms/kg/hr for 30 minutes and then 800 micrograms/kg/hr for 30 minutes) or high-dose infusion of the drug (800, 1,600 and 3,200 micrograms/kg/hr sequentially, each for 30 minutes). Hemodynamic measurements were obtained at 1 hour before amrinone and at the end of each infusion step. Low-dose infusion of amrinone resulted in a progressive increase in cardiac output (p less than 0.05) and stroke volume (p less than 0.05) and progressive reductions in pulmonary artery occluded pressure (p less than 0.01) and systemic vascular resistance (p less than 0.05). Systemic blood pressure and heart rate were unchanged. High-dose infusion resulted in a similar increase in cardiac output (p less than 0.05) but no change in stroke volume owing to associated tachycardia (p less than 0.01). There was a significantly greater decrease in pulmonary artery occluded pressure compared with the low-dose infusion (p less than 0.05), and systemic arterial diastolic and mean pressures were also decreased (p less than 0.05). The decrease in systemic vascular resistance was of a similar order to that induced by the low-dose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

The haemodynamic effects of nifedipine (20 mg sublingually) were studied in 40 patients with acute myocardial infarction within 18 h of the onset of symptoms. To determine the influence of preload and afterload on the haemodynamic response to nifedipine, patients were prospectively stratified equally into four groups of 10 patients based on systemic blood pressure level (less than or greater than 160/100 mm Hg) and level of left ventricular filling pressure [pulmonary artery-occluded pressure (PAOP) less than or greater than 18 mm Hg]. In all groups, nifedipine reduced systemic arterial pressure (p less than 0.01) and vascular resistance index (p less than 0.01); heart rate (p less than 0.01) and cardiac index (p less than 0.01) were increased. PAOP was reduced by nifedipine only in those hypertensive patients in whom it was initially raised; in these patients cardiac stroke volume index also increased (p less than 0.01). In hypertensive patients with normal PAOP the cardiac stroke work index was reduced. In patients with normal systemic and pulmonary arterial pressures, nifedipine had no beneficial effects on cardiac function. These data suggested that haemodynamic criteria may allow selection of patients for nifedipine therapy following myocardial infarction; clear advantages were evident only in hypertensive patients in both the presence and the absence of left ventricular failure.

The haemodynamic dose-response effects of intravenous amrinone were measured in 16 male patients, aged 40-65 years, with radiographic and haemodynamic evidence of left ventricular failure 4-18 h after acute myocardial infarction. After a l-h control period to confirm stable haemodynamic baseline variables, patients were randomised to either low-dose (200-400-800 micrograms/kg/h) or high-dose (800-1600-3200 micrograms/kg/h) intravenous amrinone. Each of the three infusions was given consecutively over 30 min (total infusion time 90 min) in each group, and haemodynamic measurements were made at the end of each infusion step. No arrhythmias or other untoward side effects, including haematological changes, were observed during the infusions. In both groups, intravenous amrinone reduced the pulmonary artery-occluded pressure (PAOP) (p less than 0.01), increased the cardiac output (p less than 0.05), and reduced the systemic vascular resistance (p less than 0.05). The reductions in PAOP and systemic arterial diastolic pressure and the increase in heart rate were directly dose-related, but the changes in cardiac output and systemic vascular resistance were not. These results suggest that peripheral vasodilation, particularly of venous capacitance vessels, as well as positive inotropic stimulation, may play a role in the haemodynamic changes induced by intravenous amrinone in acute ischaemic left ventricular failure.

During exercise testing, amlodipine increased the total exercise time at all three doses. The time to onset of angina was also increased at all these dose levels. These findings were noted at 6 and 24 hours after dose. Although exercise parameters appeared to show greater improvement at 6 hours after dose than at 24 hours after dose, analysis revealed that these differences were nonsignificant. The evaluation of the symptomatic profile of patients with angina by the investigator showed that amlodipine had significantly greater efficacy compared with placebo (p = 0.03). There were no severe adverse reactions to amlodipine compared with placebo. In conclusion, once-daily treatment of chronic stable angina with amlodipine is effective, and the drug is well tolerated.

The circulatory consequences of concurrent slow-calcium channel (nicardipine) and cardioselective beta blockade (metoprolol) were evaluated in 20 patients with angiographically proven coronary artery disease. The rest and exercise haemodynamic impact of intravenous nicardipine (10mg) or metoprolol (10mg) alone was determined by randomly allocating 10 patients to each drug; finally all patients were assessed on combination therapy. The plasma levels of nicardipine (17 ±3 to 53 ±6 ng ml-1) and metoprolol (36 ±5 to 97 ± 16 ng ml-1) achieved at the time of each study were in the established therapeutic range. At rest nicardipine reduced systemic mean arterial pressure and systemic vascular resistance index; cardiac and stroke volume indices increased without change in pulmonary artery occluded pressure. Metoprolol alone reduced systemic blood pressure, heart rate and cardiac index, and increased systemic vascular resistance index. Combination therapy reduced systemic arterial blood pressure and heart rate with relatively modest effects on cardiac index, systemic vascular resistance index and pulmonary artery occluded pressure.During dynamic exercise nicardipine reduced systemic mean and diastolic arterial pressure and stroke work index without change in other haemodynamic variables. Metoprolol reduced exercise systemic arterial pressures, heart rate and cardiac index, and increased systemic vascular resistance index and pulmonary artery occluded pressure. Combination therapy produced changes similar to those at rest; at peak nicardipine pharmacodynamic activity, the cardiac depressant actions of metoprolol were largely offset by the induced reduction in left ventricular afterload.Thus these data suggest that nicardipine is safe to use concurrently with cardioselective beta-adrenoceptor blockade; moreover it may prove useful in offsetting some of the adverse haemodynamic effects of beta-blocking drugs in patients with severe coronary artery disease.

The haemodynamic dose-response effects of intravenous indoramin were evaluated in 12 patients with acute heart failure (pulmonary artery occluded pressure of greater than 20 mm Hg) complicating a recent myocardial infarction. Following a 1-h control period with confirmed stable haemodynamics, the effects of three intravenous bolus doses of indoramin (0.125, 0.125, and 0.25 mg/kg at 15-min intervals) were determined in the 10- to 15-min period following each intravenous injection. Plasma drug concentrations rose with the administered dose and were in the previously established therapeutic range. Ten patients tolerated all three doses of the drug; two patients were withdrawn following the second dose owing to clinically evident hypotension (systolic blood pressure of less than 100 mm Hg). Indoramin resulted in progressive falls in systolic, diastolic, and mean systemic arterial pressures (p less than 0.01) without change in cardiac index. There was a dose-related reduction in the heart rate (0.5 mg/kg; -7 beats/min; p less than 0.01). The left ventricular filling pressure showed a significant and quadratic reduction over the dose range (0.5 mg/kg, -5 mm Hg; p less than 0.01). The systemic vascular resistance index was reduced (-333 dynes X s X cm-5 X m2; p less than 0.001) and the stroke volume index increased (+3 ml/m2; p less than 0.05) following the maximum cumulative dosage. These data established the therapeutic safety of indoramin (0.125-0.5 mg/kg) in acute heart failure following myocardial infarction. An improvement in cardiac performance in these patients was compatible with circulatory actions on both cardiac preload and afterload.