Impacto do ALLHAT

New York Times looks back at minimal impact of massive ALLHAT trialNovember 28, 2008 Shelley Wood
New York, NY - A feature story in the New York Times tracking the legacy of the ALLHAT trial reports that six years after the trial results were announced, use of diuretics remains much lower than many people predicted back in 2002 [1].
"The aftereffects of the study show how hard it is to change medical practice, even after a government-sanctioned trial costing $130 million produced what appeared to be solid evidence," Times reporter Andrew Pollack writes.
Dr Curt Furberg was chair of the study until resigning in August 2004 out of frustration over the lack of effort put into disseminating the "ALLHAT message." He told the Times that diuretic use "should have more than doubled" in recent years, since it was the safest and cheapest drug studied, with efficacy equal to that of the brand-name drugs in the trial. "The impact was disappointing," Furberg is quoted as saying in the Times.
In the massive ALLHAT trial (with more than 44 000 patients), an alpha-blocker arm of the study was stopped early after trial monitors saw a sharp uptick in heart-failure hospitalizations among patients randomized to this treatment. In the other three arms of the trial, risk of subsequent CHD death or nonfatal MI was similar among patients treated with a diuretic, a calcium-channel blocker (CCB), or an ACE inhibitor, but ACE-inhibitor-treated patients had a 15% increased risk of stroke and a 19% increased risk of heart failure, and CCB-treated patients had a 38% increased risk of heart failure. Medical advances play a role
The Times article notes that the proportion of hypertension patients treated with a diuretic rose from 30% to 35% before the ALLHAT results, to around 40% the year following their release, but prescriptions have more or less plateaued ever since. Other drugs going off patent, newer drugs coming on the market, and the introduction of combination two-in-one pills are some of the more innocuous reasons diuretics failed to gain more traction, Pollack's article notes. Quoting Dr John M Flack (Wayne State University, Detroit, MI), who was not involved in the study, the main issue probed by ALLHAT—which drug to start with in hypertensive patients—was "an outdated question that doesn't have huge relevance to the majority of people's clinical practices."
Also quoted in the article, Dr Carolyn M Clancy, director of the federal Agency for Healthcare Research and Quality, acknowledged that although randomized clinical trials are the best way to answer a question like the one tackled in ALLHAT, they are expensive and time-consuming. "You might be answering a question that, by the time you are done, no longer feels quite as relevant," she told the Times.
But Pollack's article, which runs more than 2700 words in length, also chronicles some of the less benign factors that limited the increased use of diuretics, most notably the aggressive marketing by brand-name drug-makers, like Pfizer, manufacturer of both the alpha blocker and the CCB used in ALLHAT. Court documents show that a Pfizer sales executive boasted that Pfizer employees "were quite brilliant in sending their key physicians to sightsee rather than hear Curt Furberg slam Pfizer once again!" referring to an ALLHAT presentation at an American cardiology meeting. When the ALLHAT results came out, Pfizer "set out to accentuate the positive," Pollack writes, noting that a news release, as well as a print ad in a medical journal, lauded the positive results for its CCB but failed to mention its heart-failure risk documented in the trial.
Other companies also played a role in diminishing the switch to generic diuretics, Pollack points out. In a major marketing push, Novartis spent millions promoting its new angiotensin-receptor blocker valsartan (Diovan), which was too new to have been studied in ALLHAT, the Times article notes.Modifying the message
Furberg, a long-time critic of CCBs, told the Times that "the pharmaceutical industry ganged up and attacked, discredited the findings." Indeed, the motive for some ALLHAT naysayers—including some who had leadership positions in the ALLHAT trial—may have been financial, Pollack suggests. For example, steering-committee member Dr Richard H Grimm Jr (University of Minnesota, Minneapolis) received more than $200 000 from Pfizer the year after ALLHAT came out, roughly half of which came from giving 100 Pfizer-sponsored talks about ALLHAT, he told the Times.
Others, however, suggest that government agencies "overstated" the trial results as a means of reducing medical spending, Pollack writes, quoting Dr Michael Weber (Health Science Center, Brooklyn, NY), who told the Times: "There was a feeling there was a political and economic agenda as much as a scientific agenda. They pushed beyond what the data allowed them to say."
When one adds to the controversy all of the subsequent hypertension trials that have emerged over the past six years, the result is a trial that to this day has never had the impact that many investigators expected.
Source
Pollack A. The evidence gap: The minimal impact of a big hypertension study. New York Times, November 28, 2008. Available at: http://www.nytimes.com/2008/11/28/business/28govtest.html?_r=1&scp=1&sq=ALLHAT&st=nyt.
Related links
LVEF data refine ALLHAT message to favor diuretic as HTN monotherapy [Hypertension > Hypertension; Nov 21, 2008]
ALLHAT: Detailed heart-failure analysis published [Heart failure > Heart failure; May 09, 2006]
ALLHAT: Diuretic the best bet as a first step in hypertension [HeartWire > News; Dec 17, 2002]

raiva em pernambuco

São Paulo, sexta-feira, 14 de novembro de 2008
Texto Anterior Próximo Texto Índice Brasil registra caso único de cura de raiva
Estudante de Recife foi mordido por morcego; médicos usaram técnica dos EUA, que curou adolescenteFÁBIO GUIBUDA AGÊNCIA FOLHA, EM RECIFE Um estudante de 15 anos, internado há 35 dias na UTI do Hospital Universitário Oswaldo Cruz, em Recife, foi curado de raiva, doença considerada mortal em 100% dos casos.Segundo o Instituto Pasteur, é o primeiro caso de cura comprovada da doença no país e o segundo no mundo. Um terceiro caso de cura, na Colômbia, ainda está sob investigação.O estudante foi submetido a um tratamento desenvolvido em 2004 por médicos de Milwaukee (EUA). O método, baseado em coma induzido e utilização de um antiviral, foi aplicado com sucesso em uma adolescente americana.Desde então, o mesmo tratamento foi repetido em outras 16 pessoas no mundo, mas apenas a adolescente de Milwaukee e o estudante pernambucano sobreviveram.A equipe médica de Pernambuco, no entanto, não cumpriu integralmente o protocolo de Milwaukee porque alguns dos medicamentos recomendados não estão disponíveis no Brasil.O Ministério da Saúde acompanhou o tratamento e poderá utilizá-lo como modelo no país.O estado de saúde do garoto ainda é grave. Apesar de os exames comprovarem a ausência do vírus da raiva no organismo, o jovem apresenta problemas neurológicos decorrentes da infecção. Ele permanece sedado, respira com aparelhos e se alimenta por sonda. Segundo um dos responsáveis pelo tratamento, Gustavo Trindade Henriques Filho, ainda não há como avaliar se terá seqüelas.O garoto, filho de lavradores do município de Floresta (435 km de Recife), foi mordido em casa por um morcego enquanto dormia e só começou a tomar a vacina anti-rábica quatro dias depois - mas não recebeu todas as doses necessárias, nem tomou o soro anti-rábico. Um mês depois, ele apresentou os primeiros sintomas da doença -inquietude, insônia e alterações na sensibilidade.O último laudo, divulgado ontem, confirmou o diagnóstico de cura. "Faltam agora a recuperação clínica e neurológica do paciente", disse o médico.A raiva é transmitida ao homem por meio de animais, principalmente cachorros, gatos e morcegos. Nos últimos 20 anos, o país registrou 629 casos da doença, a maioria nas regiões Nordeste e Norte

Profess: abstract

Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke
Ralph L. Sacco, M.D., Hans-Christoph Diener, M.D., Ph.D., Salim Yusuf, M.B., B.S., D.Phil., Daniel Cotton, M.S., Stephanie Ôunpuu, Ph.D., William A. Lawton, B.A., Yuko Palesch, Ph.D., Reneé H. Martin, Ph.D., Gregory W. Albers, M.D., Philip Bath, F.R.C.P., Natan Bornstein, M.D., Bernard P.L. Chan, M.D., Sien-Tsong Chen, M.D., Luis Cunha, M.D., Ph.D., Björn Dahlöf, M.D., Ph.D., Jacques De Keyser, M.D., Ph.D., Geoffrey A. Donnan, M.D., Conrado Estol, M.D., Ph.D., Philip Gorelick, M.D., Vivian Gu, M.D., Karin Hermansson, D.M.Sc., Lutz Hilbrich, M.D., Markku Kaste, M.D., Ph.D., Chuanzhen Lu, M.D., Thomas Machnig, M.D., Prem Pais, M.D., Robin Roberts, M.Tech., Veronika Skvortsova, M.D., Philip Teal, M.D., Danilo Toni, M.D., Cam VanderMaelen, Ph.D., Thor Voigt, M.D., Michael Weber, M.D., Byung-Woo Yoon, M.D., Ph.D., for the PRoFESS Study Group
ABSTRACT
Background Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens — aspirin plus extended-release dipyridamole (ASA–ERDP) versus clopidogrel.
Methods In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned.
Results A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA–ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA–ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA–ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA–ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).
Conclusions The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA–ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke.

editorial Norman Kaplan: HYVET e ONTARGET

Editorial Recent Clinical Trials
The Good, the Bad, and the Misleading Norman M. Kaplan
norman.kaplan@utsouthwestern.edu
Introduction
Results of 3 major clinical trials on the treatment of hypertension have been published recently1,2 or presented.3 In addition, the validity of data provided in an often-quoted publication of another trial4 that had a major impact on nephrological practice5 has been seriously questioned.6
First, the good trial, Treatment of Hypertension in Patients 80 Years of Age or Older,1 addressed a major unsettled issue: should antihypertensive drug therapy be given to the very elderly? The need for such a study is obvious, because people >80 years of age are the fastest growing part of our population, and systolic hypertension is almost invariable among them.7 The few data available previously on the benefit versus danger of treating them were not encouraging.8
Fortunately, Treatment of Hypertension in Patients 80 Years of Age or Older turned out very well, so well that it was stopped prematurely after an average of 1.8 years of treatment because of the strong evidence of benefit with an average blood pressure that was 15/6 mm Hg lower than in the placebo group. Death from cardiovascular disease was reduced by 23%, death from any cause by 21%, stroke by 30%, and heart failure by 64%. As with all trials, some methodologic issues are noted: (1) the subjects were healthier than most people over age 80 years; (2) only one third had isolated systolic hypertension, the usual form of hypertension in the elderly; (3) only half reached the goal of 150/80 mm Hg; and (4) therapy was limited to the diuretic indapamide and the angiotensin-converting enzyme (ACE) inhibitor perindopril.
Nonetheless, the outcome data are very impressive and will call for extension of drug treatment to patients at any age who are not suffering from terminal illness or severe dementia. The suggestive evidence that ACE inhibition may reduce the risk of Alzheimer disease by increasing degradation of amyloid-β9 will likely add to the rush toward ACE inhibitor therapy in the elderly.
The Misleading Trial
The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) compared an ACE inhibitor with an angiotensin receptor blocker (ARB) and with a combination of the ACE inhibitor and the ARB.2 The trial was patterned after the Heart Outcomes Prevention Evaluation Trial10 with the same principal investigators. It was designed to show noninferiority of the ARB to the ACE inhibitor, which was shown. In particular, the equal cardioprotection by the 2 agents should settle the claim than ARBs are less effective than ACE inhibitors for myocardial protection. The combination was associated with more progressive renal dysfunction, likely from excessive lowering of blood pressure in vulnerable patients.
In view of the equivalence of the 2 drugs, a not-surprising result, the major issue leading clinicians to choose one or the other would logically depend on adverse effects. In ONTARGET, the incidence of the most common adverse effect of ACE inhibitors, cough, was reported in only 4.2% to be the cause for discontinuation of the ACE inhibitor, whereas the same dose of the same ACE inhibitor was the cause for discontinuation in 7.3% of the Heart Outcomes Prevention Evaluation Trial (both 4.2% and 7.3% are below the usual reported incidence of cough, 10% to 15%, but the larger incidences are for the occurrence of cough and not the cause of discontinuation of treatment).
Why the lower incidence of ACE inhibitor–induced cough? The reasons are obvious and should have at least been mentioned in the discussion of ONTARGET if not taken into account in establishing the protocol. These are as follows: (1) 60% of enrollees were already on an ACE inhibitor, weeding out those who were intolerant; (2) those who were known to be intolerant to an ACE inhibitor were shunted to a parallel study, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease, which has not yet been published; and (3) ramipril was given for a 3- to 4-week run-in so that, again, those who were quickly intolerant of an ACE inhibitor were not enrolled.
Thus, the major adverse effect of ACE inhibitors was minimized by design, negating the well-known lesser adverse effect profile of ARBs. This may be the reason why the editorialist commenting on ONTARGET stated, "ARBs have more side effects than ACE inhibitors,"11 despite the common knowledge that they do not.12
The Unpublished Trial

Results of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension Trial were presented as a "late breaker" at the March 2008 meeting of the American College of Cardiology, but as of June 30, 2008, the data remained unpublished. A preliminary publication describes excellent control of blood pressure in both arms, the combined diuretic plus ACE inhibitor and the combined calcium channel blocker plus ACE inhibitor.13 The oral report indicated that the combination of ACE inhibitor and calcium channel blocker was much better than the diuretic and ACE inhibitor in reducing all of the end points.
Obviously, the publication of the results of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension Trial will be of great interest. If, as reported, it shows better effects of combining a calcium channel blocker over a diuretic, and if this finding is replicated in another large randomized, controlled trial, current practice may need to be modified.
The Bad Trial
During their review of the literature to prepare a meta-analysis of the effect of monotherapy and combination therapy of inhibitors of the renin-angiotensin system on proteinuria in patients with renal disease, Kunz et al14 stated that they, "excluded one eligible trial4 because of serious implausibilities that contact with the publishing journal could not resolve." These included a highly unusual balance in the distribution of 3 key baseline variables across 3 treatment groups, discrepancy between the reported statistical method and the results in the article, and problems with patient satisfaction. In a separate letter to the editor of The Lancet, where the original article4 was published, Kunz et al6 went even further in their critique stating, "The number and seriousness of the inconsistencies found in the Nakao article led us to wonder whether it is possible that this is only a case of extremely sloppy reporting or a hint toward more severe problems with the data." This could be of little concern except that the results have been accepted by expert nephrologists5,15 and have been incorporated into clinical practice. Perhaps the main conclusion from this unfortunate episode is that reviewers and journal editors should be much more careful before publishing novel results and much quicker to admit mistakes.
Conclusions
Large clinical trials are hard to do and expensive, so that, other than for some landmark trials sponsored by the National Institutes of Health, only pharmaceutical companies are willing to pay for them. The marketers of telmisartan, used in ONTARGET, are to be congratulated for their willingness to fund trials where their products might not be better than the comparator. However, the former editor of the British Medical Journal, Richard Smith, believes that substantial biases are virtually inherent in clinical trials and that journals should only publish critiques of trials, so they could, "prevent journals from being an extension of the marketing arm of pharmaceutical companies in publishing trials that favor their products."16
Dr Smith is not the first to call attention to the dangers of designing and reporting clinical trials. Nonetheless, clinical trials are needed to inform clinical practice, as more and more drugs are marketed. Moreover, other than occasionally from the National Institutes of Health, pharmaceutical companies are virtually the only current source of funding of large-outcome trials. Their results should be published in peer-reviewed journals, but caution must be taken in accepting their results to be more than marketing tools. Their study design should be independently reviewed before initiation, and rigorous examination of their results should be provided by peer reviewers with statistical expertise.

Acknowledgments Disclosures
None.

Footnotes The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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Warfarina vs heparina para AVC embólico

Anticoagulation After Cardioembolic Stroke
To Bridge or Not to Bridge?
Hen Hallevi, MD; Karen C. Albright, DO, MPH; Sheryl Martin-Schild, MD, PhD; Andrew D. Barreto, MD; Sean I. Savitz, MD; Miguel A. Escobar, MD; Nicole R. Gonzales, MD; Elizabeth A. Noser, MD; Kachi Illoh, MD; James C. Grotta, MD
Arch Neurol. 2008;65(9):1169-1173. Published online July 14, 2008 (doi:10.1001/archneur.65.9.noc70105).
Background Most patients with cardioembolic stroke require long-term anticoagulation. Still, uncertainty exists regarding the best mode of starting long-term anticoagulation.
Design, Setting, and Patients We conducted a retrospective review of all patients with cardioembolic stroke admitted to our center from April 1, 2004, to June 30, 2006, and not treated with tissue plasminogen activator. Patients were grouped by treatment: no treatment, aspirin only, aspirin followed by warfarin sodium, intravenous heparin sodium in the acute phase followed by warfarin (heparin bridging), and full-dose enoxaparin sodium combined with warfarin (enoxaparin bridging). Outcome measures and adverse events were collected prospectively. Laboratory values were captured from the records.
Main Outcome Measures Symptomatic hemorrhagic transformation, stroke progression, and discharge modified Rankin Scale score.
Results Two hundred four patients were analyzed. Recurrent stroke occurred in 2 patients (1%). Progressive stroke was the most frequent serious adverse event, seen in 11 patients (5%). Hemorrhagic transformation occurred in a bimodal distribution—an early benign hemorrhagic transformation and a late symptomatic hemorrhagic transformation. All of the symptomatic hemorrhagic transformation cases were in the enoxaparin bridging group (10%) (P = .003). Systemic bleeding occurred in 2 patients (1%) and was associated with heparin bridging (P = .04).
Conclusions Anticoagulation of patients with cardioembolic stroke can be safely started with warfarin shortly after stroke. Heparin bridging and enoxaparin bridging increase the risk for serious bleeding.
Author Affiliations: Department of Neurology, University of Texas at Houston Medical School (Drs Hallevi, Martin-Schild, Barreto, Savitz, Gonzales, Noser, Illoh, and Grotta) and Department of Hematology (Dr Escobar), University of Texas Health Science Center at Houston; and Department of Neuroscience, University of California, San Diego (Dr Albright).

Diabetes tipo 1 e controle intensivo

Continuous Glucose Monitoring and Intensive Treatment of Type 1 Diabetes
The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group
ABSTRACT
Background The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined.
Methods In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks.
Results The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, –0.53%; 95% confidence interval [CI], –0.71 to –0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, –0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, –0.13; 95% CI, –0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference.
Conclusions Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133 [ClinicalTrials.gov] .)

Alopurinol e hipertensão em adolescentes

Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
A Randomized Trial
Daniel I. Feig, MD, PhD; Beth Soletsky, RN; Richard J. Johnson, MD
JAMA. 2008;300(8):924-932.
Context Hyperuricemia is a predictor for the development of hypertension and is commonly present in new-onset essential hypertension. Experimentally increasing uric acid levels using a uricase inhibitor causes systemic hypertension in animal models.
Objective To determine whether lowering uric acid lowers blood pressure (BP) in hyperuricemic adolescents with newly diagnosed hypertension.
Design, Setting, and Patients Randomized, double-blind, placebo-controlled, crossover trial (September 2004-March 2007) involving 30 adolescents (aged 11-17 years) who had newly diagnosed, never-treated stage 1 essential hypertension and serum uric acid levels 6 mg/dL. Participants were treated at the Pediatric Hypertension Clinic at Texas Children's Hospital in Houston. Patients were excluded if they had stage 2 hypertension or known renal, cardiovascular, gastrointestinal tract, hepatic, or endocrine disease.
Intervention Allopurinol, 200 mg twice daily for 4 weeks, and placebo, twice daily for 4 weeks, with a 2-week washout period between treatments. The order of the treatments was randomized.
Main Outcome Measures Change in casual and ambulatory blood pressure.
Results For casual BP, the mean change in systolic BP for allopurinol was –6.9 mm Hg (95% confidence interval [CI], –4.5 to –9.3 mm Hg) vs –2.0 mm Hg (95% CI, 0.3 to –4.3 mm Hg; P = .009) for placebo, and the mean change in diastolic BP for allopurinol was –5.1 mm Hg (95% CI, –2.5 to –7.8 mm Hg) vs –2.4 (95% CI, 0.2 to –4.1; P = .05) for placebo. Mean change in mean 24-hour ambulatory systolic BP for allopurinol was –6.3 mm Hg (95% CI, –3.8 to –8.9 mm Hg) vs 0.8 mm Hg (95% CI, 3.4 to –2.9 mm Hg; P = .001) for placebo and mean 24-hour ambulatory diastolic BP for allopurinol was –4.6 mm Hg (–2.4 to –6.8 mm Hg) vs –0.3 mm Hg (95% CI, 2.3 to –2.1 mm Hg; P = .004) for placebo. Twenty of the 30 participants achieved normal BP by casual and ambulatory criteria while taking allopurinol vs 1 participant while taking placebo (P < .001).
Conclusions In this short-term, crossover study of adolescents with newly diagnosed hypertension, treatment with allopurinol resulted in reduction of BP. The results represent a new potential therapeutic approach, although not a fully developed therapeutic strategy due to potential adverse effects. These preliminary findings require confirmation in larger clinical trials

UKPDS: intensive glucose control

10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes
Rury R. Holman, F.R.C.P., Sanjoy K. Paul, Ph.D., M. Angelyn Bethel, M.D., David R. Matthews, F.R.C.P., and H. Andrew W. Neil, F.R.C.P.
ABSTRACT
Background During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.
Methods Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no

UKPDS: tight blood pressure control

Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes
Rury R. Holman, F.R.C.P., Sanjoy K. Paul, Ph.D., M. Angelyn Bethel, M.D., H. Andrew W. Neil, F.R.C.P., and David R. Matthews, F.R.C.P.
ABSTRACT
Background Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained.
Methods Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories.
Results Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02).
Conclusions The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837 [controlled-trials.com] .)

Comentário sobre o seguimento do UKPDS

Assessing the Cardiovascular Safety of Diabetes Therapies -->
Allison B. Goldfine, M.D.
-->The Endocrinologic and Metabolic Drugs Advisory Committee for the Food and Drug Administration (FDA), of which I am a member, convened in early July to consider whether data on long-term cardiovascular safety should be required for new and existing therapies for type 2 diabetes mellitus, whether trials should merely rule out harm or must show cardiovascular benefit, and at what point in the drug-approval process and by what methods cardiovascular data should be obtained.
Clinical treatment goals for patients with type 2 diabetes include alleviating acute symptoms of hyperglycemia and forestalling diabetes-related complications. Drugs that are approved by the FDA for treating diabetes are indicated for the improvement of glycemia, as measured by levels of the surrogate marker glycated hemoglobin. Improving glycemia reduces polyuria, polydipsia, polyphagia, blurred vision, general malaise, and longer-term microvascular complications, including retinopathy leading to blindness, nephropathy leading to end-stage renal disease and dialysis, and painful peripheral neuropathy. However, although increases in glycemia are associated with a greater risk of cardiovascular disease (the leading cause of illness and death among patients with diabetes), it has been difficult to prove that reducing glycemia by any drug or treatment strategy has a direct cardiovascular benefit.
Type 2 diabetes is a chronic, progressive condition, so additional safe and effective agents would have considerable clinical importance. The approval of new therapies on the basis of their reducing glycated hemoglobin levels has led to the availability of multiple new classes of agents. For decades, only insulin and sulfonylureas and, for a short while, phenformin were available, but since 1995, eight new classes of drugs have been approved for diabetes management: metformin, -glucosidase inhibitors, thiazolidinediones, glinides, glucagon-like peptide analogues, amylin analogues, dipeptidyl peptidase IV inhibitors, and bile acid sequestrants. Although metabolic control has been improved in an increasing proportion of patients and the prevalence of diabetes-related end-stage renal disease and loss of vision has been reduced, the cardiovascular and other long-term risks associated with many of these agents remain poorly characterized, rendering it difficult to make informed treatment choices.
Lately, concerns have been raised that some antidiabetes agents may impart greater cardiovascular risk than was previously appreciated. A recent meta-analysis of clinical trials of rosiglitazone (Avandia), a thiazolidinedione, pointed to an increased risk of myocardial ischemia (odds ratio, 1.43),1 which fueled debate over whether long-term cardiovascular outcome trials should be part of the approval process for diabetes drugs. Some have also questioned the safety of older therapies — particularly sulfonylureas, which have been linked to increased cardiovascular risk by both early trials2 and active surveillance of insurance databases.3 Meanwhile, the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (ClinicalTrials.gov number, NCT00000620 [ClinicalTrials.gov] ) found that a treatment strategy designed to lower blood glucose to near-normal levels was associated with increased mortality; of note, there were no apparent adverse cardiac effects of rosiglitazone.4 In contrast, no change in the rates of death or cardiovascular events was demonstrated in the Action in Diabetes and Vascular Disease: A Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial (NCT00145925 [ClinicalTrials.gov] ).5 Thus, both macrovascular effects of antidiabetes agents and the optimal glycemic goals, as well as other aspects of combined treatment strategies, remain incompletely understood.
Cardiovascular-outcome trials are not required at the time of approval of diabetes drugs (see box). Since conducting such a trial is expensive and can take years, some worry that requiring an outcome trial before marketing would delay the availability or inhibit the development of new agents. Yet delay in obtaining these data could put many patients at undue risk, and physicians and patients must choose drugs without knowledge of the risk–benefit balance.
Since, as the advisory committee agreed, it is sufficient for a diabetes drug to improve glycemia to be considered to have clinical merit, clinical trials could be designed to rule out an unacceptable increase in cardiovascular risk rather than be required to demonstrate cardiovascular benefit. Pharmacotherapy, after all, usually entails a balance between risk and benefit, and improved glycemia clearly has multiple metabolic and microvascular benefits. Moreover, absolute, relative, and population attributable risk are all important considerations.
Information for the initial assessment of potential cardiovascular risk could be improved through the development of an integrated trial design for all phase 2 and 3 preapproval trials, incorporating prespecified procedures that standardize the collection and analysis of data. The use of an independent adjudication committee for the blinded assessment of cardiovascular events would facilitate the identification of safety signals and help rule out a large excess of cardiovascular risk. Although meta-analyses of safety data from all phase 2 or 3 clinical trials of a given agent do not provide evidence of safety or risk similar to that afforded by a randomized, controlled trial, they could provide some evidence of risk during product development. Setting an upper limit for the hazard ratio in an integrated set of data from multiple preapproval trials would provide an important first safety measure. Agents for which an unacceptable cardiovascular risk signal was detected would require further evaluation before approval. Industry might opt instead to slow or discontinue product development, as occurred with muraglitazar, a dual peroxisome proliferator–activated receptor agonist.
Pharmaceutical companies often plan to initiate large-scale, randomized clinical trials to measure health outcomes after drug approval, but once the marketing goal has been achieved, the urgency to complete the study is diminished. If these studies are not conducted in a timely manner or are inadequately powered to assess safety, patients can continue to be exposed to uncertain risk indefinitely. Under the FDA Amendments Act of 2007 (FDAAA), there is increased authority for the FDA to regulate drugs after initial approval, including postmarketing clinical trials, manufacturers' labeling, and restrictions on distribution and use. The FDA could require manufacturers to submit a design for a cardiovascular-safety trial and ongoing progress reports to obtain and maintain a drug's approved status; failure to achieve milestones might lead to restrictions or withdrawal of approval. In any case, care providers should be reminded that limited safety information is available for the newest products.
Passive postmarketing-surveillance systems currently monitor for untoward drug effects. For example, MedWatch forms are supposed to be completed for adverse events that care providers believe might be drug-related. Despite a lack of uniformity in reporting, these systems can be useful for detecting rare events. However, with inherent underreporting, the lack of a comparator group, and the absence of randomization, passive surveillance is unlikely to reveal much about conditions commonly associated with the disease being treated, such as cardiovascular events in patients with diabetes. Active postmarketing surveillance, using large, linked patient registries from insurance or provider networks, is becoming more common. Although these investigations are also limited by their nonrandomized design and the incompleteness of information on potential confounders, they do provide a defined population for evaluation. Yet only outcome trials provide randomization, with its absence of bias, systematic and reliable capture of events, timely adjudication, retention for targeted duration of follow-up, and achievement of the proper dose and duration of use for assessment of the risk–benefit ratio.
Many clinical studies focus on surrogate markers for early risk assessment, but since the relationships among the underlying disease, the intervention, the surrogate, and the end-organ outcome are not always direct, findings can be misleading. In patients with diabetes and cardiovascular disease, surrogates include weight, lipid levels, blood pressure, carotid-artery intima–media thickness, endothelial function, and circulating markers of oxidant stress, among others. Although using these measures means obtaining earlier indications of risk–benefit ratios, the validity of many surrogate markers is poorly established. These studies explore mechanistic hypotheses but cannot replace outcome-based trials.
The Endocrinologic and Metabolic Drugs Advisory Committee discussed a two-step process for evaluating the cardiovascular safety of new diabetes agents. It would consist of a randomized cardiovascular-event–driven trial, before approval, to rule out an unacceptable upper confidence limit for the hazard ratio. A longer, larger trial after approval could establish the safety margin more clearly. This approach might also demonstrate a new drug's cardiovascular superiority over a comparator, with no further trial necessary. For the preliminary trial to be brief but include a sufficient number of events to permit evaluation, it would need to be performed in the highest-risk population, such as patients with diabetes who have already had a myocardial infarction, have required bypass or stenting procedures, or have an acute coronary syndrome. Such patients are highly vulnerable, however, and probably least able to tolerate adverse events. If a drug's presumed mechanism and preclinical data suggest a likelihood of substantial cardiovascular benefit for high-risk patients, this risk might be warranted; otherwise, it might be inappropriate to perform early investigations in this population.
The size and duration of any antidiabetes trial must depend on a drug's molecular mechanism and type, as well as on the number of adverse events that occurred during evaluations in vitro and in animals and humans. Finally, given the ethical importance of maintaining acceptable glycemic control for patients in long-term studies, one must carefully consider which comparators are being used. Is a drug that is used alone or in combination with other antidiabetes drugs being compared with placebo or with another drug or combination of drugs? In the absence of a single program for preapproval studies, pharmaceutical companies should work closely with the FDA to develop an individualized program.
Clearly, physicians face dilemmas regarding the use of new agents in patients with diabetes who are at high cardiovascular risk. Agents for which there are data on long-term safety should be the preferred treatments while we await information and hard-outcome trials for new agents. We must also recognize that optimal therapy for diabetes includes not only glucose lowering but also management of lipid levels, blood pressure, and platelet aggregation, which together can dramatically reduce the rate of cardiovascular events.
Dr. Goldfine participated in the Endocrinologic and Metabolic Drugs Advisory Committee meeting on July 1 and 2, 2008. All opinions expressed in this article are those of the author and do not necessarily reflect those of the other members of the advisory panel, the FDA, or the Joslin Diabetes Center.
No potential conflict of interest relevant to this article was reported.
Source Information
Dr. Goldfine is head of the Section on Clinical Research at the Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School — both in Boston.
References

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-2471. [Free Full Text]
The University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970;19:Suppl 2:747-830. [ISI]
McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf 2007;16:711-725. [CrossRef][ISI][Medline]
The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559. [Free Full Text]
The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572. [Free Full Text]

TIMI-38 Prasugrel em diabéticos

Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 Stephen D. Wiviott MD*, Eugene Braunwald MD, Dominick J. Angiolillo MD, PhD, Simha Meisel MD, Anthony J. Dalby MD, Freek W.A. Verheugt MD, Shaun G. Goodman MD, Ramon Corbalan MD, Drew A. Purdy MD, Sabina A. Murphy MPH, Carolyn H. McCabe BS, Elliott M. Antman MD, for the TRITON-TIMI 38 Investigators
Background—Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38.
Methods and Results—We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, Pinteraction=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, Pinteraction=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, Pinteraction=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, Pinteraction=0.05).
Conclusions—Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.

3 erros estatísticos

Three Statistical Errors That Are Totally Trivial but Which Matter a Great Deal
Posted 08/18/2008
Andrew J. Vickers, PhDAuthor Information MEDSCAPE
Tommy John, the renowned pitcher, once made 3 errors on a single play: He fumbled a grounder, threw wildly past first base, then bobbled the relay throw from right field and threw past the catcher. I was reminded of that story when peer-reviewing a paper describing a randomized trial. Near the start of the results section, the authors wrote something like, "Although there was no difference in baseline age between groups (P = .458), controls were significantly more likely to be male (P = .000)."
This goes one better than Tommy John, because there are actually 4 errors in this single sentence (or perhaps even 4.5).* The first error has been discussed in a previous article (please see Related Links): You cannot conclude "no difference" between groups on the basis of a high P value because failing to prove a difference is not the same as proving no difference.
Here are the other 3 errors:
P values for baseline differences between randomized groups. P values are used to test a hypothesis -- in this case, a null hypothesis that can be informally stated as: "There is no real difference between groups; any differences we see are due to chance alone." But this is a randomized trial, so any differences between groups must be due to chance alone. In short, we are testing a null hypothesis that we know to be true. Nonetheless, reporting P values for baseline differences in randomized trials remains routine: When I recently refused a clinician's request to calculate these P values for baseline differences, he sent me references to several recent papers published in high-profile journals to show that what I thought was wrong was actually quite common. Given that copying others is not necessarily the best path to statistical truth, I politely declined a second time.
Inappropriate levels of precision. The first p value in our multierror sentence is reported to 3 significant figures (P = .458). What do the 5 and 8 tell us here? We are already way above statistical significance; a little bit more or less isn't going to change our conclusions, so reporting the P value to a single significant figure (ie, P = .5) is fine. Inappropriate levels of precision are pretty ubiquitous in the scientific literature, perhaps because a very precise number sounds more "scientific." One of my favorite examples is a paper that reported a mean length of pregnancy of 32.833 weeks, suggesting that we want to know the time of conception to the nearest 10 minutes. This would require some rather close questioning of the pregnant couple.
Reporting a P value of zero. No experimental result has a zero probability; even if I throw a billion unbiased coins I have a small, but definitely non-zero, chance of getting all heads. I once pointed this out in a peer review, only to have the authors reply that the statistical software had given them P = .000, so the value must be right.
This gets to the heart of why I care about these errors even though they don't make much difference to anything (why don't I just ignore those unnecessary decimal places?). Many people seem to think that we statisticians spend most of our time doing calculations, but that is perhaps the least interesting thing that we do. Far more important is that we spend time looking at numbers and thinking through what they mean. If I see any number in a scientific report that is meaningless -- a P value for baseline differences in a randomized trial, say, or a sixth significant figure --I know that the authors are not being careful about what they are doing; they are just pulling numbers from a computer print-out. And that doesn't sound like science to me.
*Note: About that "half an error": the authors tell us that "baseline" age was no different between groups. This was a trial on pain in which all patients were on study for the same period of time, so unless patients in different treatment groups grew old at different rates, there is no reason to tell us that it is "baseline” age that is being compared

Tríplice terapia antiplaquetária aumenta risco na prevenção secundária do AVC

A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility
Nikola Sprigg, Laura J. Gray, Tim England, Mark R. Willmot, Lian Zhao, Gillian M. Sare, Philip M. W. Bath*
Abstract
Background
Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke.
Methodology/Principal Findings
A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01).
Conclusions/Significance
Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy.

Antipsicóticos e risco de AVC

Study indicates antipsychotic medications may increase stroke risk.The BBC (8/28) reported that "all forms of antipsychotics" may increase the risk of stroke, according to a study published online in the Aug. 29 issue of the BMJ. Ian Douglas, M.D., of the London School of Hygiene and Tropical Medicine in the U.K., and colleagues, "identified 6,700 patients from a" general-practitioner "database, all with an average age of 80, and concluded that there was more than a tripling of risk for dementia patients taking any sort of anti-psychotic drug." But, "patients without dementia taking any sort of antipsychotic" also "had a 40 percent increase in risk." Therefore, the authors "repeated the recommendation that patients with dementia should not be prescribed these drugs." "The risk for stroke was slightly higher for people taking the newer atypical antipsychotics, compared with people taking the older typical antipsychotics," HealthDay (8/28, Reinberg) added. "Atypical antipsychotics include drugs such as Abilify (aripiprazole), Clozaril (clozapine), and Zyprexa (olanzapine). Typical antipsychotics include Thorazine (chlorpromazine), Haldol (haloperidol), and Clopixol (zuclopenthixol)." The authors, however, did not examine "the potential mechanisms associated with antipsychotics that cause stroke, or why the risk appears higher with atypical antipsychotics."

Profess: não inferioridade de antiplaquetários

PROFESS Trial Published: Combination Therapy Falls Short of Noninferiority vs Clopidogrel
Susan Jeffrey
August 28, 2008 — In the largest secondary stroke-prevention trial to date, the combination of aspirin and extended-release (ER) dipyridamole (Aggrenox, Boehringer Ingelheim) did not meet prespecified criteria for noninferiority vs clopidogrel (Plavix/Iscover, Sanofi-Aventis/Bristol-Myers Squibb), but rates of recurrent stroke, the primary outcome, were similar between the groups.
"Therefore, the study does not show that either aspirin plus extended-release dipyridamole or clopidogrel is superior to the other in the prevention of stroke," the investigators, with first author Ralph L. Sacco, MD, from the Miller School of Medicine at the University of Miami, in Florida, conclude.
"These findings provide additional safety and efficacy data physicians need in making individual treatment decisions for prevention of recurrent stroke or the combined end point of stroke, myocardial infarction [MI], or death from vascular causes in their patients with stroke," they write.
In a factorial design, the trial also examined the effect of early blood pressure lowering after a stroke using telmisartan (Micardis, Boehringer Ingelheim) vs placebo and found no benefit of the addition of the angiotensin-receptor blocker (ARB) in prevention of stroke recurrence, major cardiovascular events, or diabetes, at least during the 2.5 years of follow-up in this study.
The results are published online as 2 papers August 27 in the New England Journal of Medicine. The findings were previously presented at the 17th European Stroke Conference, in Nice, France, and reported by Medscape Neurology & Neurosurgery at that time.
Factorial Design
The PROFESS trial included 20,332 patients from 695 sites in 35 countries. All had had a noncardioembolic ischemic stroke within the previous 120 days. They were randomized in a factorial design to receive aspirin (25 mg) plus ER dipyridamole (200 mg) twice daily or clopidogrel (75 mg) once daily. Subjects were then again randomized to receive either 80 mg per day of telmisartan or placebo.
Current guidelines in Europe and the United States recommend that for antiplatelet therapy after a stroke, aspirin, aspirin plus dipyridamole, and clopidogrel are options for prevention of stroke recurrence, but there is no recommendation for the use of 1 of these agents over the others. Direct comparison of aspirin alone vs aspirin and dipyridamole in the European and Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and the European Stroke Prevention Study 2 (ESPS2) had shown the combination to be more effective than aspirin alone without increasing major bleeding. The PROFESS trial aimed to provide information on a direct comparison of the combination vs clopidogrel.
The planned antiplatelet comparison used a sequential analysis of noninferiority first, then superiority, the researchers noted. The margin chosen for noninferiority was 1.075, or a 7.5% noninferiority difference.
In the end, the comparison for the primary outcome of recurrent stroke did not meet this predefined criterion for noninferiority, although the number of recurrent strokes was similar between the groups
PROFESS: Primary Outcome for Comparison of Aspirin Plus Extended-Release Dipyridamole vs Clopidogrel
End Point
Aspirin + ER-Dipyridamole
Clopidogrel
Hazard Ratio (95% CI)
P
Stroke recurrence, n (%)
915 (9.0)
898 (8.8)
1.01 (0.92 – 1.11)
.783
The secondary outcome, a composite of stroke, MI, and vascular death, was identical between groups, they note. Other end points, including deaths and MI, were not statistically different between groups, with the exception of new or worsening heart failure, which was significantly less frequent in the combination group.
Major hemorrhagic events were increased with the combination vs clopidogrel; intracranial hemorrhage (ICH), including 128 hemorrhagic strokes counted in the primary outcome, was significantly higher with the combination. There were no significant differences between the 2 groups in the frequency of death, any hemorrhagic event (major or minor), or thrombotic thrombocytopenia purpura or neutropenia.
PROFESS: Major Hemorrhagic Events
Event
Aspirin + ER-Dipyridamole
Clopidogrel
Hazard Ratio (95% CI)
Major hemorrhagic events, n (%)
419 (4.1)
365 (3.6)
1.15 (1.00 – 1.32)
ICH
147 (1.4)
103 (1.0)
1.42 (1.11 – 1.83)
Despite the increase in bleeds, the net risk for recurrent stroke or major hemorrhagic event was similar between the groups.
PROFESS: Benefit/Risk Analysis
End Point
Aspirin + ER-Dipyridamole
Clopidogrel
Hazard Ratio (95% CI)
P
Recurrent stroke or major hemorrhagic event, n (%)
1194 (11.7)
1156 (11.4)
1.03 (0.95 – 1.11)
.504
Adverse events leading to permanent discontinuation were increased with the combination (16.4%) vs clopidogrel (10.6%). Headache was more frequent with the combination, leading to permanent discontinuation in 5.9% of the patients on combination therapy vs 0.9% on clopidogrel.
Dr. Sacco told Medscape Neurology & Neurosurgery that this study provides more evidence that clopidogrel is as effective as ER dipyridamole and aspirin in terms of reducing recurrent stroke.
"How we choose between the 2 agents is still going to be up to clinicians," he said. "For those patients with more cardiac disease, some of us may choose clopidogrel more often, and for others we still have extended-release dipyridamole as an option."
Telmisartan vs Placebo
In a separate paper, the PROFESS researchers, with lead author Salim Yusuf, MD, from McMaster University, in Hamilton, Ontario, published results of the telmisartan-placebo comparison.
Previous studies, including the Heart Outcomes Prevention Evaluation (HOPE) and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), had shown a benefit associated with using an angiotensin-converting enzyme (ACE) inhibitor initiated late after stroke, with or without a large reduction in blood pressure. In this trial, the PROFESS researchers investigated whether using a blocker of the renin-angiotensin system, telmisartan, initiated early after a stroke, would reduce recurrent stroke.
Despite a mean blood pressure difference between the groups of 3.8/2.0 mm Hg in favor of telmisartan, there was no difference between groups on the primary end point of recurrent stroke, on secondary outcomes of a composite of major cardiovascular events (death from cardiovascular causes, recurrent stroke, MI, or new or worsening heart failure), or in new-onset diabetes.
PROFESS: Primary and Secondary Outcomes with Telmisartan vs Placebo
End Point
Telmisartan
Placebo
Hazard Ratio (95% CI)
P
Recurrent stroke, n (%)
880 (8.7)
934 (9.2)
0.95 (0.86 – 1.04)
.23
Major CV events, n (%)
1367 (13.5)
1463 (14.4)
0.94 (0.87 – 1.01)
.11
New-onset diabetes (%)
1.7
2.1
0.82 (0.65 – 1.04)
.10
Subsequent analyses suggested there may have been an effect by time, Dr. Yusuf noted when he presented these results in Nice, and the researchers speculate that the trial may have been too short to see a benefit with treatment. Suboptimal adherence in the treatment group, as well as competing use of other blood pressure–lowering agents, reduced the blood pressure differential between the groups, "which hurt our power," he said.
"What we need are longer trials, but large trials, with greater blood pressure lowering," Dr. Yusuf concluded.
A third factorial analysis of the PROFESS data, looking for any neuroprotective effects of dipyridamole, aspirin, or the ARB telmisartan in those patients who did have a recurrent stroke, was also presented at the European Stroke Conference by first author Hans-Christof Diener, MD, from the University of Duisberg-Essen, in Essen, Germany. Results of that analysis, that at least in the preliminary analysis presented in Nice showed no evidence of any such neuroprotective effects, will be published separately

Comentários sobre WENBIT

Don't End It With WENBIT -- Details Needed on B Vitamins, Stroke, and Cancer
From Heartwire — a professional news service of WebMD
August 20, 2008 — The Western Norway B-Vitamin Intervention Trial (WENBIT), showing no benefit of either folate with vitamin B12 or vitamin B6 in patients with established heart disease, is now published in the August 20, 2008, issue of the Journal of the American Medical Association [1]. First presented at the European Society of Cardiology Congress 2007 by Dr Marta Ebbing (Haukeland University Hospital, Bergen, Norway), as reported by heartwire, the trial is the latest in a series of studies suggesting that B-vitamin supplementation is not justified as secondary prevention in heart disease and that its intended target, homocysteine, is a marker of coronary heart disease (CHD), rather than a "modifiable cause" of heart disease.
Commenting on the published study to heartwire, Ebbing pointed out that the rigorous design of the WENBIT study makes the results an important addition to the field. Patients underwent coronary angiography before entering the study, were not already taking B vitamins, and Norway, unlike many other countries, does not have folic-acid fortification of foods.
"WENBIT confirms and adds further evidence to results from previously published and similar homocysteine-lowering B-vitamin trials in populations with established or at increased risk of cardiovascular disease," she said.
WENBIT results
In WENBIT, 3096 CHD patients were randomized in a 2 x 2 factorial design to one of four groups to receive a daily oral dose of folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); folic acid with vitamin B12 alone; vitamin B6 alone; or placebo. Homocysteine levels declined by about 30% in the folic-acid/B12 group at one year; the trial, however, was terminated early after results from the Norwegian Vitamin (NORVIT) trial suggested a possible increase in cancer risk with B-vitamin supplementation. After a median follow-up of 38 months, there was no significant difference in the risk of death or major cardiovascular events among the four groups.
But like the NORVIT trial before it, WENBIT hinted at a possible cancer risk — a worrying trend, given that several Western countries have or are considering mandatory folic-acid fortification of staple foods, including cereals, spreads, and flour, to prevent neural-tube defects in babies.
"Both in NORVIT and in WENBIT there was a numerically larger incidence of cancer in the groups treated with folic acid and vitamin B12, and although this could be due to chance, the possible harmful effects of folic-acid treatment/supplementation on cancer development should be explored," Ebbing told heartwire. Researchers in NORVIT and WENBIT are currently working to provide combined results from an extended follow-up of the almost 7000 patients who participated in these trials to explore such possible harmful short- and long-term effects from the intervention.
Furthermore, she said, the B-Vitamin Trialists Treatment Collaboration is planning to collaborate on a meta-analysis of results from completed and ongoing B-vitamin intervention trials. "Incident cancers will be one of the clinical end points in this analysis," she said.
There is also some suggestion that the incidence of stroke is actually reduced by folic acid/vitamin B12, and this potential effect may also warrant further scrutiny, the WENBIT investigators note.
WENBIT: Percentage of patients with cardiovascular events
End point
Folic acid+B12+B6
Folic acid+B12
B6
Placebo
Primary end point
12.2
16.3
13.7
12.5
All-cause death
4.5
4.9
3.6
3.9
Acute MI
7.7
9.9
7.1
7.4
Unstable angina
2.9
3.8
3.1
3.5
Nonfatal thromboembolic stroke
1.4
2.2
2.6
2.4
Cancer
6.0
5.1
4.9
4.0
Dr Salim Yusuf (McMaster University, Hamilton, ON), who discussed the trial when it was first presented last year, pointed out that results from the VITAmins TO Prevent Stroke (VITATOPS) trial (8000 stroke patients) and the SEARCH trial in 12,000 heart-disease patients will more than double the total database on homocysteine lowering. Echoing Ebbing et al's conclusions, Yusuf stated: "There is no reason now to lower homocysteine levels, but it is still too early to write off the hypothesis completely."
This trial was funded by the Advanced Research Program and Research Council of Norway, the Norwegian Foundation for Health and Rehabilitation, the Norwegian Heart and Lung Patient Organisation, the Norwegian Ministry of Health and Care Services, the Western Norway Regional Health Authority, the Department of Heart Disease at Haukeland University Hospital, Locus for Homocysteine and Related Vitamins at the University of Bergen, Locus for Cardiac Research at the University of Bergen, the Foundation to Promote Research Into Functional Vitamin B12 Deficiency, Bergen, Norway, and Alpharma Inc, Copenhagen, Denmark.
One study author has disclosed that he is a member of the steering board of the nonprofit Foundation to Promote Research Into Functional Vitamin B12 Deficiency. Two study authors have received consulting fees from Nycomed. The remaining study authors have disclosed no relevant financial relationships.
Source
Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography. A randomized controlled trial. JAMA. 2008;300:795-804

Vytorin e câncer: um caso para ser verificado

FDA investigating link between Vytorin and cancer.
The Wall Street Journal (8/22, B7, Favole, Mundy) reports that the Food and Drug Administration (FDA) "is reviewing a recent study, called SEAS, that found an increased risk of cancer and deaths from cancer in patients taking Vytorin (ezetimibe and simvastatin), compared with those given a placebo." The agency "expects to receive a final SEAS study report from the Merck/Schering-Plough joint venture in about three months and said it will likely take...six months to fully evaluate the data."
Investigators "involved in the SEAS study said during a July 21 press conference to discuss the data that the increased cases were likely due to chance,"
Bloomberg (8/22, Larkin, Pettypiece) adds. In order "to see if there was a risk, Richard Peto, professor of medical statistics and epidemiology at the University of Oxford, analyzed larger and longer studies of Vytorin that would be more likely to find one." But he "found no increase in cancers in those studies and concluded the SEAS finding was likely an anomaly."
The FDA "said patients should not stop taking Vytorin because the evidence of a cancer link is unclear," according to the AP (8/22, Alonso-Zaldivar, Johnson). The agency said that "while one recent clinical trial indicated higher rates of cancer for patients taking the medication, two studies currently under way have shown no increased risk." Meanwhile, "leaders of the powerful House Energy and Commerce Committee asked the companies for extensive data on the" SEAS trial. Rep. John D. Dingell (D-Mich.), who chairs the committee, "and Rep. Bart Stupak (D-Mich.), chairman of its Oversight and Investigations subcommittee, sent a letter to the chief executives of the drug companies, giving them two weeks to supply detailed information." The lawmakers "are investigating drug industry safety issues and marketing practices, and have been focusing increasingly on Vytorin." MedPage Today (8/21, Peck) and
WebMD (8/21, DeNoon) also covered the story.

Surrogate End-points: ENHANCE

Clinical Trials and Surrogate End Points: Lessons From the ENHANCE Trial
Posted 08/12/2008
John Alan Farmer, MDAuthor
The lipid hypothesis was originally proposed as a theory to explain the central role of dyslipidemia in the initiation and progression of atherosclerosis. The lipid hypothesis was supported by epidemiologic, pathologic and genetic observations. However, definitive proof of concept would require prospective clinical trial evidence that demonstrates that optimization of dyslipidemia would result in a reduction in risk from the complications of atherosclerosis. Epidemiologic studies that demonstrate a statistical correlation between dyslipidemia and atherosclerosis do not necessarily imply that pharmacologic modification of the lipid profile will alter the natural history of atherosclerosis. Early clinical trials that employed a variety of interventions did demonstrate that modification of dyslipidemia resulted in a modest decrease in the incidence of cardiovascular events. Clinical trials such as the Lipid Research Clinic Coronary Primary Prevention Trial, which utilized cholestyramine, and the Helsinki Heart Study, which analyzed gemfibrozil, demonstrated that these interventions did reduce cardiovascular event rates.[1,2] However, the interpretation and implication of these trials generated considerable controversy. The absolute degree of risk reduction was minimal and total mortality was not improved. The failure of pharmacologic therapy to reduce total mortality despite a decline in cardiovascular mortality implied a potential drug-mediated adverse effect of cholesterol lowering that would negate the vascular benefits. The early clinical trials were also hampered by problems in trial design and only a modest improvement in circulating lipid levels. The advent of pharmacologic agents that partially inhibit the key enzyme in cholesterol synthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase) provided the ability to significantly reduce LDL levels. Statin therapy was originally approved by the US FDA solely with an indication to improve dyslipidemia since clinical trial evidence for event reduction was lacking at the time of approval. The role of statin therapy in cardiovascular risk reduction was subsequently studied in a variety of clinical trials that encompassed the spectrum of atherosclerosis. The role of cardiovascular risk factor modification in primary prevention (clinical absence of atherosclerosis) has been controversial owing to economic, efficacy and safety concerns. Primary prevention can be subdivided into high- and low-risk populations depending on the degree of dyslipidemia and extent of associated risk factors. Statin therapy was subsequently demonstrated to be efficacious in both high- and low-risk subgroups. The West of Scotland Coronary Primary Prevention Study analyzed the role of pravastatin therapy in a patient cohort characterized by significant dyslipidemia coupled with a high prevalence of other risk factors, such as tobacco usage.[3]
Pravastatin therapy demonstrated a clear reduction in the incidence of cardiovascular events. The Air Force/Texas Coronary Atherosclerosis Prevention Study evaluated the role of lovastatin therapy in a large cohort of both men and women with LDL-C levels that were considered to be within normal limits by contemporary guidelines.[4] The primary lipid abnormality was a reduced level of HDL. Lovastatin therapy significantly reduced the primary end point, which was a composite consisting of sudden death, fatal and nonfatal myocardial infarction and unstable angina. The role of statin therapy in secondary prevention (documented presence of atherosclerosis) was evaluated in patients who survived a myocardial infarction coupled with a significantly elevated LDL-C level in the Simvastatin Scandinavian Survival Study (4S).[5] Simvastatin therapy reduced not only cardiovascular but also total mortality. Additionally, pravastatin therapy was demonstrated to reduce cardiovascular events in survivors of a myocardial infarction whose total cholesterol levels were considered to be normal (<240 mg/dl) in the Cholesterol and Recurrent Events (CARE) study.[6] Analysis of secondary prevention studies demonstrated a linear reduction in cardiovascular event rates, which correlated with the degree of reduction in LDL-C levels (Figure 1). Additionally, multiple vascular imaging (angiography, intravascular ultrasound, B-mode ultrasound etc.) studies have analyzed the impact of modification of the lipid profile on the progression of coronary atherosclerosis. Intravascular ultrasound studies have been performed, which compared aggressive lipid-lowering strategies with a more conventional approach.[7] The intensive reduction of LDL-C has been correlated with reduced plaque volume. The controversy relative to the clinical benefits, which accrue from the reduction of LDL-C levels, appeared to have been resolved and the concept that ‘lower is better’ achieved widespread acceptance. Many experts felt that further clinical trials demonstrating the reduction of hard clinical end points following lipid-lowering therapy were no longer required owing to the extensive clinical trial experience involving thousands of patients. Clinical trials require large numbers of subjects followed for a period of years and are extremely expensive to perform. The problems associated with enrolment and funding of clinical trials has led to the concept of the substitution of surrogate markers a satisfactory means to demonstrate clinical benefit. However, the utilization of surrogate markers is problematic. The problems encountered by relying upon surrogate markers were emphasized in the recent clinical controversy surrounding the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study.

Secondary prevention trials and LDL reduction.
The ENHANCE trial was designed to study the potential benefits of the addition of the cholesterol absorption inhibitor ezetimibe to maximum statin dosing on the progression of atherosclerosis.[8] The ENHANCE trial is a randomized, double-blind active comparator study, which employed a surrogate marker (B-Mode ultrasound) in lieu of clinical end points such as myocardial infarction. The progression of atherosclerosis was assessed by the utilization of B-mode ultrasonography imaging to calculate the intimal medial thickness of the carotid and femoral arteries.
The modification of intimal medial thickness is not recognized by the US FDA as an end point qualifying for drug approval or a new drug indication. The rationale for combination therapy lies in the fact that the greatest reduction in LDL-C occurs with the initial statin dose. Subsequent doubling of the dose results in approximately a 5-7% additive reduction in LDL reduction and is associated with an increased incidence of side effects.[9] The therapeutic rationale for the addition of ezetimibe is to further reduce circulating LDL levels as a means of achieving goals established by the National Cholesterol Education Program (NCEP). Ezetimibe lowers LDL by reducing the absorption of cholesterol from the gastrointestinal tract by binding to the Niemann-Pick C1-like 1 protein, which is the key transport mediator.[10] The reduction in the delivery of cholesterol to the liver results in a decrease in intrahepatic cholesterol followed by an upregulation of the LDL receptor. The increase in LDL-receptor activity is associated with enhanced plasma clearance of lipoproteins that carry ApoB or ApoE on their surface. The gastrointestinal absorption of cholesterol is at least partially under genetic control and the average individual absorbs approximately 55% of the cholesterol presented to the gastrointestinal tract. The administration of ezetimibe monotherapy results in a 15-20% reduction in LDL-C in the individual with normal absorptive capacity. The use of ezetimibe is associated with minimal systemic toxicity owing to the limited absorption and enterohepatic circulation. The ENHANCE study compared simvastatin 80 mg plus ezetimibe 10 mg versus simvastatin 80 mg alone on carotid and femoral intimal thickness. The study population was composed of 720 subjects with heterozygous familial hypercholesterolemia who were evaluated over a 24-month trial period. The trial was well designed and conducted by a research group that is highly experienced in the analysis of carotid intimal thickness. The baseline characteristics of the patients were well matched, with the exception of a higher prevalence of increased BMI in the simvastatin plus ezetimibe group.
Combination therapy resulted in a significant reduction in circulating lipid levels compared with the group who received simvastatin alone. The circulating levels of LDL-C decreased from 317.8 to 192.7 mg/dl in the simvastatin alone group. Combination therapy reduced circulating LDL-C levels from 319.0 to 141.3 mg/dl and represented a between-group difference of 16.5%, which was statistically significant. Combination therapy also resulted in a significant reduction in high-sensitivity C-reactive protein (hs c-RP) protein of 49% compared with 23% in the simvastatin monotherapy group. The primary end point of the EHANCE study was the change from baseline in the mean intimal thickness of the carotid artery. Combination therapy did not result in a significant alteration of the primary end point for simvastatin monotherapy (0.0058 ± 0.0037 versus 0.0111 ± 0.0038; p = 0.29). Additionally, a variety of secondary end points were not beneficially altered by combination therapy. New plaque formation, which was defined as intimal medial thickness in excess of 1.3 mm, was demonstrable in 2.8% of the monotherapy group and 4.7% of subjects who received combination therapy (p = 0.20). The addition of combination therapy also did not beneficially alter intimal thickness in the femoral arteries. The ENHANCE study thus evaluated three surrogate markers that have been correlated with risk for atherosclerosis (LDL-C, c-RP and carotid intimal thickness). The hypothesis that reduction of LDL-C and inflammatory markers would result in a beneficial duration of carotid intimal thickness was not verified. How can these surprising results be explained?
The possibility of technical problems in the assessment of carotid intimal thickness is highly unlikely. Physicians involved in the analysis of the images are considered to be world experts. Additionally, the research group that designed and performed the ENHANCE trial previously performed the well-regarded Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) study. The ASAP and EHANCE studies both analyzed subjects with heterozygous familial hypercholesterolemia. The ASAP trial was designed to compare the effects of atorvastatin 80 mg with simvastatin 40 mg on carotid intimal thickness in 320 subjects over a 2-year period.[11] The study populations in the ASAP and ENHANCE trials was similar in age, lipid profile and method employed to quantitate carotid intimal thickness. The ENHANCE and ASAP trials both utilized the same central core laboratory for image evaluation. However, carotid intimal thickness at baseline was not the same in the two groups. The ASAP cohort had carotid intimal thickness of 0.925 mm compared with 0.695 mm in the ENHANCE cohort. The normal value for carotid intimal thickness in subjects 40-49 years of age is 0.64 mm at the bifurcation of the common carotid. The values for carotid intimal thickness in the ENHANCE study were essentially normal at baseline implying prior significant risk factor modification (especially considering the high-risk patient population, which was composed of heterozygous familial hypercholesterolemic subjects in their fifth decade of life) prior to the onset of the study.
The ASAP trial was begun in 1997 when aggressive therapy with statins was less prevalent. The number of patients in the ASAP trial who previously were treated with statins and the duration of therapy is not available. By contrast, 80% of subjects in the EHANCE study had previously received statin therapy and only a short washout period was employed. The possibility of a lengthy period of pretreatment with statins resulting in delipidation of the vasculature in the EHANCE cohort may have blunted potential benefits from a further 24-month treatment period.
Assuming that there were no technical problems encountered in the accumulation and analysis of the data, a major question to be answered is the validity of the surrogate end points that were analyzed in the ENHANCE trial as a means of predicting risk from atherosclerosis. The clinical utility of a surrogate marker would require confirmation that the substitution of a laboratory measurement (LDL-C, carotid intimal thickness etc.) is a substitute for clinically meaningful end points, such as reduction of cardiovascular events.
Thus, definite proof should be present to demonstrate the changes induced by any therapeutic intervention on a surrogate end point accurately predict a clinically meaningful outcome alteration. The ENHANCE trial is basically an analysis of several biomarkers on the process of atherosclerosis with carotid intimal thickness designated as the primary end point. LDL-C, c-RP and other lipid subfractions were significantly reduced. A major question is which of the analyzed surrogates is the most valid in predicting risk from atherosclerosis? The major lipid alteration in the ENHANCE trial was a highly significant reduction in LDL-C by the combination of simvastatin and ezetimibe of 51 mg/dl, which was statistically significant with a p-value of less than 0.01. LDL reduction has consistently been correlated with a decrease in cardiovascular event rates in multiple trials. LDL-C and c-RP have extensive databases that support their use as surrogate end points.[12] The utility of employing the rate of change in carotid intimal thickness is conceptually attractive as it directly analyzes vascular structure but lacks the robust database of LDL-C modification and clinical end point reduction. Modest positive statistical correlations between the degree of carotid intimal thickness and event rates have been demonstrated in 30 of 34 clinical studies.[13] The role of lipid therapy in the modification of carotid intimal thickness has been analyzed in 15 clinical studies and has demonstrated that high-dose statin therapy has slowed or caused regression of atherosclerosis.[14] However, studies with less than 2 years of follow-up have not demonstrated event reduction, which raises the possibility that short-term studies such as the ENHANCE trial may not be valid in the utilization of intimal thickness as a surrogate marker. A major clinical question that was raised by the ENHANCE trial also relates to the efficacy of ezetimibe. The result of the trial has been interpreted by some as evidence that the addition of ezetimibe provides no benefit in reducing the risk of atherosclerosis either in combination or monotherapy. Ezetimibe has been demonstrated to reduce the degree of atherosclerosis in experimental animals, which may not be applicable to human subjects. However, ezetimibe has been demonstrated to exhibit several proatherogenic effects, including inhibition of the scavenger receptor B1 and decreasing the activity of the ATP-binding cassette A1, which modulates the efflux of cholesterol from the lipid-laden macrophage.[15] However, for these mechanisms to exhibit clinically relevant proatherogenic activity, ezetimibe would require significant systemic activity and the drug is only minimally absorbed from the gastrointestinal lumen.
Additionally, LDL-lowering interventions (fibric acid derivatives, nicotinic acid, bile acid sequestrants, diet and ileal bypass) have all been demonstrated to reduce clinical events.
The major exception is the cholesterol ester transfer protein inhibitors, such as torcetrapib, which improved the lipid profile but demonstrated adverse affects such as the induction of hypertension. Ezetimibe has not been correlated with the worsening of any metabolic effects due to the lack of systemic absorption.
The controversy surrounding the ENHANCE trial may have been avoided by the formation and presence of an external advisory board to independently analyze the design of the trial with modification of the aforementioned problems. The null results of the trial are difficult to translate into clinical practice guidelines. The NCEP guidelines remain valid and appropriate LDL goals should still be attempted to be achieved. Statin therapy should remain the primary therapeutic intervention. If combination therapy is required, utilization of agents with a proven clinical efficacy should be employed. Ezetimibe therapy may still be added to achieve LDL goals when statin monotherapy is inadequate or associated with side effects such as myopathy. The clinical benefits of combination therapy utilizing statins and ezetimibe will await the results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, which will analyze the affect of combination therapy on hard end points.[16] The IMPROVE-IT trial will provide insight into the role of absolute LDL reduction in addition to clarification of the role and efficacy of the therapies employed to achieve LDL goals.


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