Researchers at the University of Pennsylvania School of Medicine say preliminary results of a small study show promise in improving erectile dysfunction (ED) in men who had shown minimal reaction to Viagra. The study results are published in the March issue of the "Journal of Sexual Medicine."

Erectile dysfunction is often a sign of a more severe vascular problem that involves abnormalities in the lining of the blood vessels. And often, endothelial dysfunction is an underlying problem for ED - it can be one of the first signs of atherosclerosis, a build-up of plaque and blockages in the arteries.

"It's already known that there is a connection between erectile dysfunction and coronary disease. The risk factors are the same for both, and thus, ED can be a marker for coronary disease," explains lead author Howard Herrmann, MD, Professor of Medicine and Director of the Interventional Cardiology and Cardiac Catheterization Laboratories at the Hospital of the University of Pennsylvania. "Normal erections are caused when nitric oxide is made, but with endothelial dysfunction, the body doesn't make enough of it, causing the erectile dysfunction. Normally, Viagra prevents the breakdown of the little nitric oxide that is there, so that there is enough of it for an erection to occur."

However, about 10-30 % of men are classified as "Viagra non-responders" - in these men, Viagra did not significantly help their erectile dysfunction. So in a small, double blind, randomized, placebo-controlled study at Penn, Herrmann looked at a dozen patients with ED who had not responded well to Viagra. He gave them either a high-dose Lipitor or a placebo. He then rechallenged them with Viagra and asked if the ED had improved.

"There did seem to be some improvement for those who received Lipitor versus the placebo," said Herrmann. "We theorized that if you could make the edothelium healthier through the use of statins — so that there is more nitric oxide available — you would improve the endothelial dysfunction and Viagra would work better for the patient."

And there are other potential benefits too. Stan Schwartz, MD, Director of the Diabetes Disease Management program at Penn and co-author, states, "Patients with Diabetes, both Type 1 and Type 2, are plagued with complications of the diabetic state that involve endothelial dysfunction. This research points us in a direction that says any drug class that improves endothelial dysfunction may also be beneficial to patients with diabetes."

Additionally, Emile Mohler, MD, Director of Vascular Medicine at Penn and co-author, cautions, "ED is a sign that cholesterol plaque may be present in the heart, neck or leg arteries. Men with ED should be evaluated for vascular disease."

"These preliminary results show promise," adds Herrmann. "They support the hypothesis that erectile dysfunction may be one sign of a generalized vascular disorder characterized by endothelial dysfunction and that statin drugs may improve the endothelial dysfunction, even before altering the lipid profile. But the results are preliminary and warrant further testing in a larger clinical trial," he cautions.

It should be noted that beyond endothelial dysfunction, there are other reasons Viagra may not work well for someone.

The results of this study were published in the March 2006 issue of the "Journal of Sexual Medicine." Members can access the journal on-line at: <http://jsm.issir.org>. The article is titled, "Can Atorvastatin Improve the Response to Sildenafil in Men with Erectile Dysfunction Not Initially Responsive to Sildenafil? Hypothesis and Pilot Trial Results."

This study was supported by an unrestricted medical center grant from Pfizer.

About Penn's School of Medicine

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

http://www.uphs.upenn.edu
This is a part of article Statins Improve Erectile Performance Of Some Men Who Previously Did Not Respond Well To Viagra Taken from "Purchase Sildenafil Citrate" Information Blog

Methods

Study Design

As shown in Figure 1, for the initial 12 weeks of treatment, eligible patients were randomized in a 3:1 ratio to receive induction therapy, 4 mg of r-hGH dosed daily (group A, DD) or PL (group B, PL). At week 12, subjects in group A were rerandomized in a 1:1 ratio to receive maintenance therapy, 2 mg of r-hGH on AD or PL on AD, from weeks 12 through 36. Subjects from group A, on r-hGH induction and r-hGH maintenance, are referred to as the DD-AD-AD group; those from group A on induction therapy with r-hGH followed by PL maintenance are the DD-PL-PL group. Subjects in group B, who received PL from baseline to week 24 and then received 4 mg/d of r-hGH for weeks 24 through 36, are the PL-PL-DD group.

Figure 1.  (click image to zoom)

Study design.      

The prespecified primary efficacy parameter was the absolute change from baseline to week 12 in area of VAT on a cross-sectional computed tomography (CT) scan at L4-L5. Secondary efficacy endpoints included changes in other body composition parameters, serum lipids, body image, and quality-of-life variables (results for body image and quality of life are reported separately).[13]

Safety data included glucose and insulin parameters, viral load, CD4 cell counts, adverse events (AEs), insulin-like growth factor (IGF)-I and its main binding protein (IGF-BP3), hemoglobin A1c (HbA1c; an indicator of adequacy of glucose control over a 3-month period),[14] and standard hematologic and clinical chemistry parameters.

The primary prespecified criterion of efficacy for maintenance therapy at week 36 was maintenance failure rate, defined as the proportion of subjects originally given 4 mg/d of r-hGH 4 for weeks 1 through 12 who succeeded in losing VAT during baseline to week 12 but then regained more than 50% of their VAT loss by week 36 (see statistical analysis). Failure rates were also compared between those assigned to PL or 2 mg of r-hGH on AD for weeks 12 through 36. Mean changes from baseline to week 36 in VAT, other body composition parameters, lipid profile, and safety parameters were also examined.

Randomization was stratified by gender and implemented by a central system operated by an independent vendor (Clinphone, Nottingham, United Kingdom), assigning patients to treatment using a blinded computer-generated randomization list. The trial was conducted according to the Declaration of Helsinki principles and Good Clinical Practice. Independent institutional review boards approved the protocol at each site. Written informed consent was obtained from each patient before screening.Study Subjects

Eligibility criteria were the same as for the previous trial.[5] Patients were between 18 and 60 years old, had documented HIV infection, had been on stable antiretroviral therapy (ARVT) for ≥30 days, and agreed to continue on ARVT while on study. They also had fasting glucose <110 mg/dL, 2-hour postload glucose on oral glucose tolerance testing (OGTT) results <140 mg/dL, and evidence of excess abdominal adipose tissue as determined by waist/hip ratio (WHR) ≥0.95 and waist circumference (WC) >88.2 cm for men and WHR ≥0.90 and WC >75.3 cm for women.[5] The WHR criteria are similar to those identified as indicative of abdominal adiposity in the literature on obesity and are known to be associated with increased cardiovascular risk.[15,16]

Patients were excluded if they had active systemic infection, unstable or untreated hypertension (≥140/90 mm Hg), acute illness treated in an intensive care unit, a history of pancreatitis, carpal tunnel syndrome (unless resolved by surgical release), diabetes mellitus, malignancy (except for limited cutaneous Kaposi sarcoma or excised basal cell or squamous cell skin carcinoma), angina pectoris, coronary artery disease, or any disorder associated with moderate to severe edema. Patients must not have been receiving insulin or insulin-sensitizing agents, systemic glucocorticoids, or weight reduction agents for 3 months before screening or therapy for HIV-associated wasting (eg, anabolic steroids other than testosterone replacement, appetite stimulants, r-hGH) for 12 months before screening. Lipid-lowering agents were permitted if they were started at least 8 weeks before study entry.Treatment and Assessment

The 4-mg induction dose of r-hGH (Serostim; EMD Serono, Rockland, MA) and its PL were given as 1.0-mL single subcutaneous injections each evening. The 2-mg AD maintenance dose of r-hGH and its PL were given as single 0.5-mL subcutaneous injections every other evening. Active and PL study drug were labeled and packaged identically, and doses were sequentially numbered. Patients were taught to self-inject according to the prescribed sequence. The protocol for dose adjustments for weight and toxicity was the same as used previously.[5]

Study visits were scheduled at screening; baseline; and weeks 2, 4, 12, 16, 24, 26, 28, and 36. CT and dual x-ray absorptiometry (DXA) scans to assess fat distribution were obtained at baseline, week 12, and week 36. OGTT and lipid profiles were obtained after a minimum 12-hour fast. These and serum IGF-I, IGF-BP3, HIV-1 RNA, and testosterone levels and CD4 T-cell count were obtained at baseline, week 12, week 24, and week 36. HbA1c levels were assessed at baseline and weeks 4, 12, and 36 by affinity chromatography. At each visit, standard hematologic and biochemistry panels, physical examinations, and reporting of AEs using the Medical Dictionary for Regulatory Activities (MedDRA), version 8.0 (MSSO, Reston, VA) were conducted. Laboratory testing was performed centrally (Esoterix Laboratories, Calabasas Hills, CA).Statistical Analysis

Data were analyzed in the modified intention-to-treat (ITT) population, which included subjects who received at least 1 dose of study drug and who had follow-up data. There were separate analysis plans for the initial 12-week induction treatment period and the 24-week maintenance period. The week 12 analysis was the primary analysis. The primary efficacy parameter, change from baseline to week 12 in absolute area of VAT, was analyzed using a nonparametric ANCOVA model with effects for treatment and gender, with baseline VAT as a covariate. The major efficacy endpoint for the maintenance phase of the study was the percentage of patients regaining >50% of the VAT they had lost during induction (weeks 1-12). Maintenance therapy was considered efficacious if, during maintenance (weeks 12-36), no more than half of the subjects who had lost VAT regained >50% of the amount they lost. Mean changes in VAT, other body composition parameters, and lipid parameters were examined in the ITT sample from baseline to week 36 and from weeks 12 to 36 as well. The trial was not powered statistically to test differences in changes in study endpoints between maintenance groups, however.

Between-group differences in continuous secondary efficacy parameters were analyzed using raw data with an ANOVA model, including effects for treatment, gender, and treatment-by-gender interaction, when parametric model assumptions were met or, using ranked data, when parametric assumptions were not met. Within-group differences were analyzed using the Wilcoxon signed rank test. Safety results were summarized for the population of patients who received at least 1 dose of study drug and had follow-up data (n = 325 for induction, n = 258 for maintenance). Between-group differences in categoric variables were analyzed using the Fisher exact test.  Printer- Friendly Email This

J Acquir Immune Defic Syndr.  2007;45(3):286-297.  ©2007 Lippincott Williams & Wilkins
This is a part of article Recombinant Human Growth Hormone to Treat HARS Taken from "Actos Pioglitazone" Information Blog

Food and Drug Administration Approvals, March 2003

from Medscape Pharmacists

Antidepressants

Effexor XR (venlafaxine hydrochloride) Extended Release Capsules

Manufacturer: Wyeth-Ayerst

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 02/11/03)

New Indication:Effexor XR (venlafaxine hydrochloride) is now indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV [300.23]).

Social anxiety disorder is characterized by a marked and persistent fear of 1 or more social or performance situations that necessitate exposure to unfamiliar people or to possible scrutiny. Exposure to the feared situation usually provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacologic treatment.

Dosing: For the treatment of social anxiety disorder, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials, Effexor XR was started at a dose of 75 mg/day and the maximum dose was 225 mg/day.

The Effexor XR labeling recommends titrating the starting dose at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day.

Clinical Summary: A total of 551 adult patients with social anxiety disorder were studied in two 12-week double-blind, parallel group, multicenter, placebo-controlled, flexible-dose studies. The efficacy of long-term treatment with Effexor XR beyond 12 weeks has not been studied. The dose of Effexor XR ranged from 75-225 mg/day.

Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score.

Adverse Effects: The most common adverse events reported in the social anxiety disorder clinical trials included: nausea (4%), insomnia (3%), headache (2%), and somnolence (2%). Impotence was reported in 3% of the men who participated in the trial (n = 158).Reference

Effexor XR (venlafaxine hydrochloride) Extended Release Capsules LabelingMedscape DrugInfo

Effexor XR (venlafaxine hydrochloride) Extended Release Capsules

This is a part of article Food and Drug Administration Approvals, March 2003 Taken from "Purchase Sildenafil Citrate" Information Blog

A New Drug for PAH: Clinical Pharmacology of Ambrisentan

In June 2007, the FDA approved ambrisentan (LETAIRIS) for the once-daily treatment of PAH to improve exercise capacity and delay clinical worsening.

Ambrisentan, a diphenyl propionic acid derivative ( Figure 1. PubChem CID:6918493), represents a valuable addition to the treatment alternatives for this orphan disease, which include prostacyclin (Flolan), inhaled nitric oxide, iloprost (a prostacyclin analog), sildenafil (a PDE5 inhibitor), and conventional Ca++ channel blockers (e.g., verapamil and nifedipine). Ambrisentan is orally active and similar to an existing drug, bosentan;[5] both are competitive inhibitors of endothelin receptors and are termed endothelin receptor antagonists (ERAs). However, bosentan lacks the receptor selectivity of ambrisentan. Ambrisentan exhibits ∼100-fold greater selectivity for endothelin receptor A (ETA) as compared to endothelin receptor B (ETB) [Ki = 0.6 nM for the human ETA receptor, 49 nM for the ETB receptor].[4] This moderate selectivity for the ET receptor may provide therapeutic advantages compared to bosentan. A common adverse effect of ERAs is the propensity to impair liver function in some patients. Thus, ambrisentan is not recommended for use in patients with moderate or severe hepatic impairment since it may cause additional liver damage.[6] Liver aminotransferase enzymes (ALT and AST) must be measured before initiation of therapy and at least monthly thereafter during therapy. The drug is an FDA category X pregnancy drug and is contraindicated in women who are or who may become pregnant. It is not known whether the drug is secreted in milk, therefore nursing mothers should not breastfeed while receiving the drug. Because of the risks of liver injury and birth defects, ambrisentan is only available through the Letairis Education and Access Program (LEAP); only prescribers and pharmacies registered with LEAP may prescribe and dispense the drug, and only patients enrolled in and meeting all conditions of LEAP may receive the drug (for enrollment information, call 866-663-5327).

Figure 1.  (click image to zoom)

Adult dosing is initiated with 5 mg once daily, and if tolerated, dosing is increased to 10 mg once daily. Although early clinical trials showed no significant differences in beneficial effects using different doses of ambrisentan (1-10 mg) for patients with PAH,[7] the results of two recent clinical trials, ARIES-1 and ARIES-2, showed a dose-dependent improvement in 6-minute walk distance with once a day ambrisentan after 12 weeks. The absolute bioavailability of ambrisentan in humans is unknown, but is ∼90% in dogs.[7a] Bioavailability is unaffected by food. The drug is rapidly absorbed after oral administration with peak plasma concentrations occurring between 1.7 and 3.3 hours. The terminal half-life is about 15 hours, but after long-term daily dosing the effective half-life is about 9 hours.[49] At steady-state, mean trough concentrations of drug are ∼15% of mean peak concentrations. The drug is highly bound to plasma proteins and elimination is primarily by non-renal pathways. In vitro data indicate ambrisentan is a potential substrate of P-glycoprotein (P-gp), the Organic Anion Transport Protein (OATP), CYP3A4, CYP2C19, and uridine glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. Because in vivo data regarding drug interactions of ambrisentan with strong inhibitors or inducers of these transporters and metabolizing enzymes are very limited, caution is advised in co-administering drugs known to affect these entities. Concomitant administration of ambrisentan with warfarin in PAH patients had no effect on PT or INR; no adjustments in dose of warfarin or ambrisentan are required when co-administered.[49] Similarly, no dose adjustments are required when ambrisentan is co-administered with sildenafil.[49] Available in vitro and in vivo pharmacokinetic data indicate hepatic impairment is likely to prolong the elimination of ambrisentan. The drug is not recommended for patients with moderate to severe liver disease, and patients with mild pre-existing hepatic impairment may require reduced dosing. Based on clinical data, no dose adjustment is required in patients with mild to moderate renal impairment, but data in patients with severe renal disease are currently unavailable.[49]

Clinical studies have indicated ambrisentan and other ERAs cause a decrease in hemoglobin and hematocrit during the first few weeks of therapy, which then stabilizes. The cause of the decrease in hemoglobin is not known, but is not due to bleeding or hemolysis. Hemoglobin measurements are required prior to ambrisentan therapy and monthly thereafter. Another ERA class effect is peripheral edema, but this is also a consequence of PAH. In the clinical studies with ambrisentan, there was an increase in peripheral edema in patients taking 5 or 10 mg daily compared to placebo, but this was typically mild to moderate in severity. Most other adverse drug reactions seen in the clinical studies were mild to moderate; discontinuation of treatment due to adverse events other than those related to pulmonary hypertension was similar for drug and placebo (∼2%).[49]Pathophysiology of PAH

PAH is defined hemodynamically as a mean pulmonary arterial pressure of =25 mmHg with a pulmonary capillary wedge pressure of =15 mmHg, both measured at rest by right-heart catheterization. Elevated pulmonary arterial pressure in PAH patients is caused by increased pulmonary vascular resistance (PVR) as a result of severe pulmonary vascular remodeling, sustained pulmonary vasoconstriction, and in situ thrombosis in small arteries. Excessive vascular remodeling, manifested by obliteration of small arteries, muscularization of precapillary arterioles, intimal lesions and fibrosis, and the plexiform lesion, is the major contributor to the elevated PVR in most patients, while sustained vasoconstriction contributes to the elevated PVR in 15-20% of PAH patients. Vasoconstriction, by itself, is also a stimulus of pulmonary artery smooth muscle cell hypertrophy and hyperplasia. Loss of pulmonary vascular compliance and increased PVR due to pulmonary vascular remodeling leads to progressively pronounced pulmonary hypertension and has indeed been found to be the predominate pathological finding in idiopathic PAH.[1]Endothelin and Endothelin Receptors in PAH

Endothelin (ET) is a 21-amino acid peptide exhibiting three isoforms ET-1, ET-2, and ET-3 ( Figure 2, Figure 3, PDB ID: 1EDN). ET-1 is a potent vasoconstrictor, mitogen, and proinflammatory mediator. In the pulmonary circulation, increased ET-1 plasma levels correlate with changes in arterial pressure.[9,10] In patients with PAH, the level of ET-1 in the plasma and pulmonary microvasculature is increased as much as 10-fold and its concentrations correlate with pulmonary artery pressure and severity of disease.[10-13] The actions of endothelins in the vasculature are mediated by at least three different G-protein coupled receptors, the ETA receptor and two ETB receptor subtypes, ETB1 and ETB2.[20,21] ETA receptors bind ET-1 and ET-2 with a higher affinity than ET-3 (order of potency: ET-1 = ET-2 > ET-3), while ETB receptors have similar affinities for all three endothelin isoforms (i.e., order of potency is ET-1 = ET-2 = ET-3). ETA and ETB are functionally expressed in various tissues with different proportions. There are at least two studies demonstrating that expression of smooth muscle cell ETB receptors is increased in PAH,[13,16] while other studies demonstrate that the endothelial ETB receptors are downregulated or dysfunctional.[17,18] Furthermore, the endothelial ETB receptor-mediated ET clearance remains intact in patients with idiopathic PAH, and only modestly reduced in patients with PAH associated with connective tissue diseases (e.g., scleroderma).[19] These studies seem to suggest that increased ET concentration in the plasma and lung tissue serves as an important stimulus for sustained pulmonary vasoconstriction and excessive vascular remodeling in patients with PAH. Selective blockade of the endothelin receptors (e.g., ETA) that mediate contractile and mitogenic effects on PASMC, while maintaining (or preserving) the function of the endothelin receptors (e.g., ETB) that cause vasodilative effects and induce ET-1 clearance, is therefore a good strategy for designing therapeutic approaches for patients with PAH, and may offer more benefits than nonselective ETA/ETB antagonists.

Figure 2.  (click image to zoom)

Amino acid sequence of ET-1. Dotted lines show arrangement of intramolecular disulfide bonds.      

Figure 3.  (click image to zoom)

The 3-D structure of human ET-1 determined by x-ray crystallography.      

  Printer- Friendly Email ThisReferencesRubin LJ: Primary pulmonary hypertension. N Engl J Med 336:111-117, 1997 8988890Runo JR, Loyd JE: Primary pulmonary hypertension. Lancet 361:1533-1544, 2003 12737878Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S-12S, 2004 15194173Billman GE: Ambrisentan (Myogen). Curr Opin Investig Drugs 3:1483-1486, 2002 12431023Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896-903, 2002 11907289Langleben D: Endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. 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Cardiovascular

correspondence questions PROactive conclusions

Susan Jeffrey
January 11, 2006

London, UK - Correspondence in the January 7, 2006 issue of the Lancet raises questions about the conclusions of the recently published Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial.

PROactive compared treatment with pioglitazone (Actos, Takeda Pharmaceutical Company/Eli Lilly) vs placebo in patients with type 2 diabetes at high risk for macrovascular events. The main results, published in the October 8, 2005 issue of the Lancet, showed a nonsignificant 10% reduction in the study's primary end point of all macrovascular events vs placebo but found a significant 16% reduction in the secondary composite end point of death, MI, and stroke with pioglitazone treatment [1].

The authors' conclusion that pioglitazone "reduces the composite of all-cause mortality, nonfatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events" draws fire from Lancet readers in this week's issue.
Concerns about interpretation

Several letters took issue with the fact that this conclusion was based largely on results from the secondary composite end point. For example, Dr Pierre-Jean Guillausseau (University Paris, France) points out, "Although the study is globally negative, a new 'main secondary end point' appeared?ie, a new composite not described in the study protocol published in 2004. The conclusions of the study are based solely on this composite. [2]"

The results should be adjusted for mean differences in hemoglobin A1c (HbA1c) and blood pressure, and there remains a major concern about the increased incidence of heart failure seen with pioglitazone, Guillausseau adds. "Thus several questions remain, and the role of glitazones in type 2 diabetes mellitus is not yet fully defined."

In a separate letter, Drs Peter Gaede, Hans-Henrik Parving, and Oluf Pedersen (Steno Diabetes Center, Copenhagen, Denmark) point out that patients receiving pioglitazone had a greater decrease in HbA1c than those on placebo, although LDL increased with treatment. However, blood pressure was also lower in treated patients, by about 3 mm Hg [3].

"An accurate prediction of the relative risk reduction of a 3-mm-Hg systolic gradient seen in PROactive indicates that this is more than sufficient to explain the whole potential cardiovascular benefit of pioglitazone," they write. "Furthermore, it should be stressed that this prediction is conservative, since diabetic patients are particularly blood-pressure sensitive."
"Hypothesis generating," not "groundbreaking proof"

Drs John S Yudkin (University College London, UK) and Nick Freemantle (University of Birmingham, UK) are blunter [4]. In concentrating on the "main secondary end point," they write, the PROactive authors "ignore the statistically neutral primary outcome. One assumes that, had the 10% reduction in primary-end-point events been significant, Dormandy and colleagues would have felt no need to emphasize the analysis of the main secondary end point," an end point that should be considered "hypothesis-generating" rather than "groundbreaking proof."

An appropriate conclusion from PROactive, Yudkin and Freemantle assert, "is that glitazones reduce cardiovascular event rates with a point estimate of around 10% to 15%, but with a confidence interval including zero?a result in line with the equally uncertain reduction in macrovascular events seen in the United Kingdom Prospective Diabetes Study (UKPDS). Judging from the way in which the results were presented at the European Association for the Study of Diabetes in Athens in September 2005 and from the website (http://www.proactive-results.com), there is a risk that the marketing division of Takeda and Eli Lilly will use these questionable results mercilessly in their promotional material."

Freemantle also voiced his objection to the PROactive conclusions in a letter previously published by the BMJ [5].

Finally, Drs RR Holman, R Retnakaran, A Farmer, and R Stevens (Churchill Hospital, Oxford UK) write that they carried out an analysis using the UKPDS Outcomes Model to assess the expected outcomes given the risk-factor changes reported [6]. They point out that the nonsignificant 10% relative risk reduction seen with pioglitazone treatment on the primary end point was less than the 20% or more on which the power calculation for the study was based.

"Our analysis supports the explanation that any macrovascular benefits seen reflect the modest improvements obtained in established risk factors, with little evidence that changes seen previously in novel risk factors with pioglitazone have any substantive effect," they write. "More worryingly, the estimated macrovascular benefits are offset by an increased risk of heart failure and concerns about increased peripheral revascularization rates."
The authors respond

In a response undersigned by the principal investigator of the PROactive study, Dr John Dormandy (St Georges Hospital, London, UK), the PROactive investigators defend their interpretation of the main secondary end point [7]. "As described in the PROactive report, this end point was prespecified in the statistical analysis plan and submitted to the Food and Drug Administration before unblinding," they write. "It showed a 16% relative risk reduction with pioglitazone (p=0.027).

"We agree that in isolation this finding would not allow any definite conclusion to be drawn," Dormandy et al add. "However, the primary composite end point, which also included silent myocardial infarction, acute coronary syndrome, major leg amputation, and coronary and leg revascularization, also showed a reduction with pioglitazone?10% relative risk reduction (p=0.095)."

To the comment made by Yudkin and Freemantle about how they would have felt no need to present the main secondary-end-point analysis if the primary end point had been significantly positive, they respond, "On the contrary, it is the effect on mortality, myocardial infarction, and strokes that would be of most interest to patients and the regulatory authorities."

As for the increase in heart failure, they point out that the heart-failure events in this study were unadjudicated and the diagnoses made by the investigators, "who might have been sometimes misled by the known increase in edema with pioglitazone," Dormandy et al write.

"We are surprised by the comparison in the Comment [the editorial accompanying the PROactive publication by Dr Hannele Yki-J¿rvinen (University of Helsinki, Finland) (8)] of first events for end points avoided, on the positive side, vs all episodes of heart failure, on the negative side," they add. "Nevertheless, the executive committee is further exploring the issue of heart failure by setting up an independent commission of experts to review, in a blinded way, all source material for patients reported to have had fatal or nonfatal heart failure at any time during the trial."
Disclosure information is provided for correspondents and PROactive authors in the Lancet publication.

Sources

Dormandy JA, Charbonnel B, Eckland DJA, et al on behalf of the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomized controlled trial. Lancet 2005; 366:1279-1289. Guillausseau PJ. PROactive study. Lancet¿2006;¿367:23. Gaede P, Parving HH, and Pedersen O. PROactive study. Lancet¿2006;¿367:23-24. Yudkin JS, Freemantle N. PROactive study. Lancet¿2006;¿367:24-25. Freemantle N. How well does the evidence on pioglitazone back up researchers' claims for a reduction in macrovascular events? BMJ 2005; 331:836-838. Holman RR, Retnakaran R, Farmer A, and Stevens R. PROactive study. Lancet¿2006;¿367:25-26. Dormandy J. PROactive study?Authors' reply. Lancet¿2006;¿367:26-27. Yki-J¿rvinen H. The PROactive study: some answers, many questions. Lancet 2005; 366:1241-1242.
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