tag:blogger.com,1999:blog-10065107772590101362024-03-13T10:19:35.689-03:00Ensaios ClínicosAnonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.comBlogger26125tag:blogger.com,1999:blog-1006510777259010136.post-8300225971288793192009-01-27T20:52:00.000-02:002009-01-27T20:53:56.829-02:00BNP vs Symptom Heart Failure<div align="justify"><strong>BNP-Guided vs Symptom-Guided Heart Failure Therapy<br />The Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) Randomized Trial</strong> </div><div align="justify"><span style="font-size:85%;">JAMA Vol. 301 No. 4, January 28, 2009<br />Matthias Pfisterer, MD; Peter Buser, MD; Hans Rickli, MD; Marc Gutmann, MD; Paul Erne, MD; Peter Rickenbacher, MD; André Vuillomenet, MD; Urs Jeker, MD; Paul Dubach, MD; Hansjürg Beer, MD; Se-Il Yoon, MD; Thomas Suter, MD; Hans H. Osterhues, MD; Michael M. Schieber, MD; Patrick Hilti, MD; Ruth Schindler, RN; Hans-Peter Brunner-La Rocca, MD; for the TIME-CHF Investigators</span><br /><strong>JAMA. 2009;301(4):383-392</strong>.<br />Context It is uncertain whether intensified heart failure therapy guided by N-terminal brain natriuretic peptide (BNP) is superior to symptom-guided therapy.<br />Objective To compare 18-month outcomes of N-terminal BNP–guided vs symptom-guided heart failure therapy.<br />Design, Setting, and Patients Randomized controlled multicenter Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) of 499 patients aged 60 years or older with systolic heart failure (ejection fraction 45%), New York Heart Association (NYHA) class of II or greater, prior hospitalization for heart failure within 1 year, and N-terminal BNP level of 2 or more times the upper limit of normal. The study had an 18-month follow-up and it was conducted at 15 outpatient centers in Switzerland and Germany between January 2003 and June 2008.<br />Intervention Uptitration of guideline-based treatments to reduce symptoms to NYHA class of II or less (symptom-guided therapy) and BNP level of 2 times or less the upper limit of normal and symptoms to NYHA class of II or less (BNP-guided therapy).<br />Main Outcome Measures Primary outcomes were 18-month survival free of all-cause hospitalizations and quality of life as assessed by structured validated questionnaires.<br />Results Heart failure therapy guided by N-terminal BNP and symptom-guided therapy resulted in similar rates of survival free of all-cause hospitalizations (41% vs 40%, respectively; hazard ratio [HR], 0.91 [95% CI, 0.72-1.14]; P = .39). Patients' quality-of-life metrics improved over 18 months of follow-up but these improvements were similar in both the N-terminal BNP–guided and symptom-guided strategies. Compared with the symptom-guided group, survival free of hospitalization for heart failure, a secondary end point, was higher among those in the N-terminal BNP–guided group (72% vs 62%, respectively; HR, 0.68 [95% CI, 0.50-0.92]; P = .01). Heart failure therapy guided by N-terminal BNP improved outcomes in patients aged 60 to 75 years but not in those aged 75 years or older (P < .02 for interaction)<br />Conclusion Heart failure therapy guided by N-terminal BNP did not improve overall clinical outcomes or quality of life compared with symptom-guided treatment.<br />Trial Registration isrctn.org Identifier: <a href="http://www.controlled-trials.com/ISRCTN43596477">ISRCTN43596477</a><br />). </div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-29313988969968832662009-01-21T00:22:00.000-02:002009-01-21T00:23:03.696-02:00VADTVADT published: Intensive glucose control fails to reduce cardiovascular eventsDecember 18, 2008 <a href="http://www.theheart.org/viewAuthorBio.do?primaryKey=114633" rel="external_author" jquery1232508078031="4">Michael O'Riordan</a><br />Phoenix, AZ - Results of the Veterans Affairs Diabetes Trial (VADT), a long-term study of US veterans with type 2 diabetes receiving intensive blood glucose control, is now published online December 17, 2008 in the New England Journal of Medicine [<a href="http://www.theheart.org/article/929765.do#bib_1">1</a>].<br />First presented at the American Diabetes Association (ADA) 2008 Scientific Sessions in San Francisco, CA and reported by heartwire at that time, the VADT showed that intensive blood glucose lowering in patients with elevated glycated hemoglobin A1c (HbA1c) levels despite medical treatment had no significant effect on the rates of cardiovascular events, death, or microvascular complications.<br />"We picked the toughest group of patients we could find because we figured if we could do some good there the benefit would be pretty obvious," lead VADT investigator Dr William Duckworth (Phoenix Veterans Affairs Health Care Center, AZ) told heartwire. "As the results show, though, we weren't able to do any good."<br />The results of the study are in line with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease (ADVANCE) studies. The ADVANCE trial showed a reduction in the progression of albuminuria with intensive glucose control but no effect on cardiovascular event rates. ACCORD, on the other hand, was stopped early because of an increased risk of death in patients who underwent intensive blood glucose lowering.Tough-to-treat patients<br />Speaking with heartwire, Duckworth said that when the VADT was initiated nearly five years ago, there was little to no evidence that glucose control altered the risk of cardiovascular events. Some studies, including the United Kingdom Prospective Diabetes Study (UKPDS), suggested improvements in microvascular end points, but there were no effects on hard clinical end points such as mortality or MI.<br />In VADT, investigators randomized 1791 military veterans with diabetes, mean age 60 years, who had a suboptimal response to medical therapy to intensive glucose control or standard glucose control. At the time of randomization, median HbA1c levels were 9.4%. In addition, nearly 75% of patients had hypertension, 40% had a previous cardiovascular event, and patients had been diagnosed with diabetes for a mean 11.5 years.<br />In both study groups, obese patients were started on two drugs, metformin and rosiglitazone, whereas nonobese patients were started with glimepiride plus rosiglitazone. Patients in the intensive arm started on maximal doses. Insulin was added to most participants to achieve HbA1c levels less than 6.0% in the intensive-treatment arm and less than 9.0% in the standard-therapy arm.<br />After a median follow-up of 6.5 years, median HbA1c levels were reduced to 8.4% in the standard-lowering arm and to 6.9% in the intensive-glucose-control arm. During this time, 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group experienced a major cardiovascular event, the composite primary end point consisting of MI, stroke, death from cardiovascular causes, congestive heart failure, vascular surgery, inoperable coronary disease, and amputation for ischemic gangrene.<br />"One of the things we wanted to do was reduce or eliminate as many controllable risk factors as we possibly could," said Duckworth. "We treated blood pressure and lipids very intensely and got those down to very good numbers. We also had the patients on aspirin and encouraged diet and exercise—all the things that you're supposed to do—and once that was done, I was not surprised that glucose lowering had no additional effect. Maybe a little disappointed, but not particularly surprised."<br />Commenting on the results for heartwire, Dr Roger Blumenthal (Johns Hopkins, Baltimore, MD) pointed out that tight glycemic control earlier in the disease process—ACCORD, ADVANCE, and VADT were carried out in individuals with established disease for a mean duration of eight to 11 years—might have been more successful.<br />Dr Sherita Golden (Johns Hopkins) echoed Blumenthal's sentiments.<br />"We all do still wonder if tight control earlier after diagnosis is most beneficial. After an individual has had diabetes for a prolonged time, the horse is out of the barn, so to speak, and tight glucose control is not as effective," said Golden.<br />She added that getting HbA1c levels down to 7% is still effective in preventing macrovascular complications, "so tight control to this level is still beneficial." In addition, tight control of blood pressure and cholesterol are proven strategies for primary and secondary prevention of cardiovascular disease in diabetes, she said.<br />Position statement on intensive glycemic control issued<br />With the publication of VADT and the earlier publications of ACCORD and ADVANCE, the ADA, American Heart Association (AHA), and American College of Cardiology (ACC) issued a position and scientific statement on intensive glycemic control and the prevention of cardiovascular events [<a href="http://www.theheart.org/article/929765.do#bib_2">2</a>].<br />"The lack of significant reduction in cardiovascular disease events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1c less than 7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications," write first author Dr Jay Skyler (University of Miami, FL) and colleagues in the statement, published online December 17, 2008 in Circulation.<br />The report emphasizes the importance of controlling nonglycemic risk factors, such as blood pressure and lipids (using statins), as well as using aspirin and lifestyle modifications as the primary strategies for reducing the burden of cardiovascular disease in people with diabetes.<br />The group states that based on ACCORD, ADVANCE, and VADT, there is no need for major changes in glycemic-control targets but does offer some "clarification of the language that has consistently stressed individualization."<br />Lowering HbA1c levels to <7% to reduce microvascular and neuropathic complications in type 1 and 2 diabetes remains a class I recommendation. Less than 7% is also a reasonable target for reducing the risk of macrovascular complications, a class IIb recommendation, at least until more evidence becomes available, they add.<br />The scientific statement is also published in the Journal of the American College of Cardiology and Diabetes Care.Treat the cardiovascular risk factors<br />Regarding the clinical implications of the study, Duckworth, like the ADA, AHA, and ACC, emphasized the importance of treating blood pressure and lipid abnormalities to reduce the risk of cardiovascular and microvascular complications from diabetes. He added that VADT, as well as ACCORD and ADVANCE, included older patients and that younger patients might be treated differently.<br />"I have a practice with my elderly patients, those older than 60 years or 65 years, to not try to get their A1c down to very low levels," he said. "If I have a 45-year-old patient, then I'm considerably more aggressive—again, we don't have any evidence that it makes difference, but these patients have much longer to live and have much more time to develop complications. It's reasonable to think they might benefit from lower glucose levels. It's one of those patient-specific things: we really should be treating patients and not numbers."<br />The ADA, AHA, and ACC also emphasize the importance of individualizing treatment. In its statement, the group notes that for those with a short duration of disease, long life expectancy, and no significant cardiovascular disease, a more aggressive HbA1c goal might be appropriate, whereas for older patients, those with advanced microvascular and macrovascular disease, less stringent targets are recommended. These last two recommendations have weak evidence supporting them and are based on consensus opinion of experts, case studies, or standards of care.<br />In their paper, the VADT investigators suggest that one possibility for the lack of observed effect of intensive therapy could be that the cardiovascular benefit is delayed. Ten-year data from UKPDS showed that early intensive glucose lowering, either with a sulfonylurea or metformin, reduced the risk of MI or all-cause mortality. Long-term follow-up from the Diabetes Control and Complications Trial—Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) study also showed a reduction in cardiovascular events in patients whose blood sugar was lowered most.<br />"If you can manage to get glucose down without risking severe hypoglycemia, then I think it's a good thing to do regardless," said Duckworth. "It might make a difference long term, even though we don't have definite proof of it."<br />Duckworth reports consulting fees from Novo Nordisk, GlaxoSmithKline, and Caremark and lecture fees from Sanofi-Aventis.<br />Sources<br /><a name="bib_1"></a>Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; DOI: 10.1056/NEJMoa0808431. Available at: <a href="http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.nejm.org" target="_blank">http://www.nejm.org</a>. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19092145&dopt=Abstract" target="_blank"></a><br /><a name="bib_2"></a>Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation 2008; DOI: 10.1161/CIRCULATIONAHA.108.191305. Available at: <a href="http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fcirc.ahajournals.org" target="_blank">http://circ.ahajournals.org</a>. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19095622&dopt=Abstract" target="_blank"></a>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-45636228960215529932009-01-02T11:43:00.001-02:002009-01-02T11:44:45.782-02:00FDA e prasugrel<a style="COLOR: #000000" name="S1"> <strong>FDA asks panel of heart doctors for help reviewing blood-thinning drug prasugrel.</strong></a><br />The <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" href="http://links.mkt1066.com/ctt?kn=60&m=3841245&r=Mjk1MjkxMTYzMwS2&b=0&j=MTA3NDYzNDcwS0&mt=1&rt=0" target="_blank" name="articles_custombriefings_com_a(3)">Wall Street Journal</a> (1/2, Rockoff, subscription required) reports that the Food and Drug Administration's (FDA) Cardiovascular and Renal Drugs Advisory Committee is set to meet on Feb. 3, and while details of the panel's agenda were not available, Eli Lilly and partner Daiichi Sankyo say that the body will discuss "whether to finally approve prasugrel," the company's "powerful anti-clotting drug and would-be competitor to blockbuster Plavix. ... Early this year, lots of folks were brimming with anticipation for prasugrel, a more powerful clot-fighter than Plavix. But the Lilly medicine also carried a higher risk for life-threatening bleeding. Perhaps no surprise then that there was a three-month delay in FDA's review earlier this year, then another with a less clear timetable for action, as the agency weighed what to do." The Journal predicts that the drug will soon be on the market in Europe, but expressed doubt that the FDA will automatically follow suit.<br /> The <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" href="http://links.mkt1066.com/ctt?kn=12&m=3841245&r=Mjk1MjkxMTYzMwS2&b=0&j=MTA3NDYzNDcwS0&mt=1&rt=0" target="_blank" name="articles_custombriefings_com_a(4)">AP</a> (1/2) also reports on the upcoming meeting, noting that prasugrel is "a potential blockbuster drug that has been plagued by regulatory delays." Prasugrel "is considered crucial to Lilly as it faces a wave of patent expirations in the next few years. Lilly previously told investors it expects to begin selling prasugrel in the first half of 2009, but declined to set a specific date for FDA approval."Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-31486931352481025402008-12-02T13:58:00.000-02:002008-12-02T13:59:18.402-02:00Impacto do ALLHAT<div align="justify">New York Times looks back at minimal impact of massive ALLHAT trialNovember 28, 2008 <a href="http://www.theheart.org/viewAuthorBio.do?primaryKey=115691" rel="external_author" jquery1228233446640="5">Shelley Wood</a><br />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 [<a href="http://www.theheart.org/article/925171.do#bib_1">1</a>].<br />"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.<br />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.<br />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<br />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."<br />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.<br />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.<br />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<br />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.<br />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."<br />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.<br />Source<br /><a name="bib_1"></a>Pollack A. The evidence gap: The minimal impact of a big hypertension study. New York Times, November 28, 2008. Available at: <a href="http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.nytimes.com%2F2008%2F11%2F28%2Fbusiness%2F28govtest.html%3F_r%3D1%26scp%3D1%26sq%3DALLHAT%26st%3Dnyt" target="_blank">http://www.nytimes.com/2008/11/28/business/28govtest.html?_r=1&scp=1&sq=ALLHAT&st=nyt</a>.<br />Related links<br /><a href="http://www.theheart.org/article/922911.do" target="_blank">LVEF data refine ALLHAT message to favor diuretic as HTN monotherapy</a> [Hypertension > Hypertension; Nov 21, 2008]<br /><a href="http://www.theheart.org/article/696257.do" target="_blank">ALLHAT: Detailed heart-failure analysis published</a> [Heart failure > Heart failure; May 09, 2006]<br /><a href="http://www.theheart.org/article/263451.do" target="_blank">ALLHAT: Diuretic the best bet as a first step in hypertension</a> [HeartWire > News; Dec 17, 2002]</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-2984439035622647152008-11-14T11:54:00.000-02:002008-11-14T11:55:11.784-02:00raiva em pernambuco<div align="justify"><br />São Paulo, sexta-feira, 14 de novembro de 2008<br /><a href="http://www1.folha.uol.com.br/fsp/saude/sd1411200801.htm">Texto Anterior</a> <a href="http://www1.folha.uol.com.br/fsp/saude/sd1411200803.htm">Próximo Texto</a> <a href="http://www1.folha.uol.com.br/fsp/saude/inde14112008.htm">Índice</a> Brasil registra caso único de cura de raiva<br />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</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-21911746838159121282008-09-24T07:33:00.001-03:002008-09-24T07:36:03.621-03:00Profess: abstract<div align="justify"><strong>Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke<br /></strong><span style="font-size:78%;">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<br /></span>ABSTRACT<br /><strong>Background</strong> 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.<br /><strong>Methods</strong> 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.<br /><strong>Results</strong> 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).<br /><strong>Conclusions</strong> 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.</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-76331405128924209802008-09-18T12:00:00.003-03:002008-09-18T12:03:52.553-03:00editorial Norman Kaplan: HYVET e ONTARGET<div align="justify">Editorial <strong>Recent Clinical Trials</strong><br />The Good, the Bad, and the Misleading Norman M. Kaplan<br /><a href="mailto:norman.kaplan@utsouthwestern.edu">norman.kaplan@utsouthwestern.edu</a><br />Introduction<br />Results of 3 major clinical trials on the treatment of hypertension have been published recently<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R1-117473">1,2</a><a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R2-117473"></a> or presented.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R3-117473">3</a> In addition, the validity of data provided in an often-quoted publication of another trial<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R4-117473">4</a> that had a major impact on nephrological practice<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R5-117473">5</a> has been seriously questioned.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R6-117473">6</a><br />First, the good trial, Treatment of Hypertension in Patients 80 Years of Age or Older,<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R1-117473">1</a> 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.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R7-117473">7</a> The few data available previously on the benefit versus danger of treating them were not encouraging.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R8-117473">8</a><br />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.<br />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-β<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R9-117473">9</a> will likely add to the rush toward ACE inhibitor therapy in the elderly.<br />The Misleading Trial<br />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.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R2-117473">2</a> The trial was patterned after the Heart Outcomes Prevention Evaluation Trial<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R10-117473">10</a> 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.<br />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).<br />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.<br />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,"<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R11-117473">11</a> despite the common knowledge that they do not.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R12-117473">12</a><br />The Unpublished Trial </div><div align="justify">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.<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R13-117473">13</a> 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.<br />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.<br />The Bad Trial<br />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 al<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R14-117473">14</a> stated that they, "excluded one eligible trial<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R4-117473">4</a> 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 article<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R4-117473">4</a> was published, Kunz et al<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R6-117473">6</a> 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 nephrologists<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R5-117473">5,15</a><a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R15-117473"></a> 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.<br />Conclusions<br />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."<a href="http://hyper.ahajournals.org/cgi/content/full/52/4/608#R16-117473">16</a><br />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.<br /><a name="ACK"></a><br />Acknowledgments Disclosures<br />None.<br /><a name="FN"></a><br />Footnotes <a name=""></a>The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.<br /><a name="BIBL"></a><br /></div><div align="justify"><span style="font-size:85%;">References<br /></span><a name="R1-117473"></a><br /><span style="font-size:85%;">Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008; 358: 1887–1898.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=358/18/1887"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R2-117473"></a><span style="font-size:85%;"><br />The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008; 358: 1547–1559.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=358/15/1547"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R3-117473"></a><span style="font-size:85%;"><br />Jamerson KA, Bakris GL, Dahlof B, Pitt B, Velazquez E, Weber MA, ACCOMPLISH Investigators. Avoiding cardiovascular events through combination therapy in patients living with systolic hypertension, the early termination of the ACCOMPLISH Trial for Efficacy. 57th Annual Scientific Session of the American College of Cardiology; Late Breakers (plus oral presentation; abstract 407-2); March 29, 2008; Chicago, IL.</span><a name="R4-117473"></a><span style="font-size:85%;"><br />Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin- converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. 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JAMA. 2002; 287: 1003–1010.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=jama&resid=287/8/1003"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R8-117473"></a><span style="font-size:85%;"><br />Bulpitt CJ, Beckett NS, Cooke J, Dumitrascu DL, Gil-Extremera B, Nachev C, Nunes M, Peters R, Staessen JA, Thijs L; Hypertension in the Very Elderly Trial Working Group. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens. 2003; 21: 2409–2417.</span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=10.1097/00004872-200312000-00030&link_type=DOI"><span style="font-size:85%;">[CrossRef]</span></a><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=14654762&link_type=MED"><span style="font-size:85%;">[Medline]</span></a><span style="font-size:85%;"> </span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=14654762&displayid=154956&link_type=INFOTRIEVE"><span style="font-size:85%;">[Order article via Infotrieve]</span></a><a name="R9-117473"></a><span style="font-size:85%;"><br />Kehoe PG, Wilcock GK. Is inhibition of the renin-angiotensin system a new treatment option for Alzheimer’s disease? Lancet. 2007; 6: 373–378.</span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=10.1016/S1474-4422(07)70077-7&link_type=DOI"><span style="font-size:85%;">[CrossRef]</span></a><a name="R10-117473"></a><span style="font-size:85%;"><br />The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=342/3/145"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R11-117473"></a><span style="font-size:85%;"><br />McMurray JJV. ACE inhibitors in cardiovascular disease – unbeatable? N Engl J Med. 2008; 358: 1615–1616.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=FULL&journalCode=nejm&resid=358/15/1615"><span style="font-size:85%;">[Free Full Text]</span></a><a name="R12-117473"></a><span style="font-size:85%;"><br />Matchar DB, McCrory DC, Orlando LA, Patel MR, Patel UD, Patwardhan MB, Powers B, Samsa GP, Gray RN. Systemic review: comparative effectiveness of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008; 148: 16–29.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=annintmed&resid=148/1/16"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R13-117473"></a><span style="font-size:85%;"><br />Jamerson K, Bakris GL, Dahlof B, Pitt B, Velazquez E, Gupte J, Lefkowitz M, Hester A, Shi V, Kjeldsen SE, Cushman W, Papademetriou V, Weber M, for the Accomplish Investigators. Exceptional early blood pressure control rates: the ACCOMPLISH Trial. Blood Press. 2007; 16: 80–86.</span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=10.1080/08037050701395571&link_type=DOI"><span style="font-size:85%;">[CrossRef]</span></a><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=17612905&link_type=MED"><span style="font-size:85%;">[Medline]</span></a><span style="font-size:85%;"> </span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=17612905&displayid=154956&link_type=INFOTRIEVE"><span style="font-size:85%;">[Order article via Infotrieve]</span></a><a name="R14-117473"></a><span style="font-size:85%;"><br />Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin-angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008; 148: 30–48.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=annintmed&resid=148/1/30"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R15-117473"></a><span style="font-size:85%;"><br />Griffin KA, Bidani AK. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade. Clin J Am Soc Nephrol. 2006; 1: 1054–1065.</span><a href="http://hyper.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=clinjasn&resid=1/5/1054"><span style="font-size:85%;">[Abstract/Free Full Text]</span></a><a name="R16-117473"></a><span style="font-size:85%;"><br />Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005; 2: e138.</span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=10.1371/journal.pmed.0020138&link_type=DOI"><span style="font-size:85%;">[CrossRef]</span></a><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=15916457&link_type=MED"><span style="font-size:85%;">[Medline]</span></a><span style="font-size:85%;"> </span><a href="http://hyper.ahajournals.org/cgi/external_ref?access_num=15916457&displayid=154956&link_type=INFOTRIEVE"><span style="font-size:85%;">[Order article via Infotrieve]</span></a></div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-36569521818231910562008-09-12T16:16:00.000-03:002008-09-12T16:17:06.278-03:00Warfarina vs heparina para AVC embólico<div align="justify"><strong>Anticoagulation After Cardioembolic Stroke<br /></strong>To Bridge or Not to Bridge?<br /><span style="font-size:85%;">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</span><br />Arch Neurol. 2008;65(9):1169-1173. Published online July 14, 2008 (doi:10.1001/archneur.65.9.noc70105).<br />Background Most patients with cardioembolic stroke require long-term anticoagulation. Still, uncertainty exists regarding the best mode of starting long-term anticoagulation.<br />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.<br />Main Outcome Measures Symptomatic hemorrhagic transformation, stroke progression, and discharge modified Rankin Scale score.<br />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).<br />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.<br />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).</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-3338539354779551012008-09-12T16:06:00.001-03:002008-09-12T16:09:35.014-03:00Diabetes tipo 1 e controle intensivo<strong>Continuous Glucose Monitoring and Intensive Treatment of Type 1 Diabetes<br />The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group</strong><br />ABSTRACT<br />Background The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined.<br />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.<br />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.<br />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 <a href="http://content.nejm.org/cgi/external_ref?access_num=NCT00406133&link_type=CLINTRIALGOV">[ClinicalTrials.gov]</a> .)Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-40095060432159213712008-09-12T15:36:00.001-03:002008-09-12T15:37:50.036-03:00Alopurinol e hipertensão em adolescentes<div align="justify">Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension<br />A Randomized Trial<br />Daniel I. Feig, MD, PhD; Beth Soletsky, RN; Richard J. Johnson, MD<br />JAMA. 2008;300(8):924-932.<br />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.<br />Objective To determine whether lowering uric acid lowers blood pressure (BP) in hyperuricemic adolescents with newly diagnosed hypertension.<br />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.<br />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.<br />Main Outcome Measures Change in casual and ambulatory blood pressure.<br />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).<br />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</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-66924662353658063182008-09-10T20:36:00.001-03:002008-09-10T20:39:54.449-03:00UKPDS: intensive glucose control<div align="justify"><strong>10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes</strong><br /><span style="font-size:85%;">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</span>.<br />ABSTRACT<br />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.<br />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 </div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com1tag:blogger.com,1999:blog-1006510777259010136.post-24176344104488477162008-09-10T20:34:00.002-03:002008-09-10T20:36:51.543-03:00UKPDS: tight blood pressure control<div align="justify"><strong>Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes</strong><br /><span style="font-size:85%;">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.<br /></span>ABSTRACT<br />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.<br />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.<br />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).<br />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 <a href="http://content.nejm.org/cgi/external_ref?access_num=ISRCTN75451837&link_type=ISRCTN">[controlled-trials.com]</a> .)<br /></div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-25122494287812371322008-09-10T20:28:00.001-03:002008-09-10T20:31:13.958-03:00Comentário sobre o seguimento do UKPDS<div align="justify"><strong>Assessing the Cardiovascular Safety of Diabetes Therapies --></strong><br />Allison B. Goldfine, M.D.<br />-->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.<br />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.<br />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.<br />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),<a href="http://content.nejm.org/cgi/content/full/359/11/1092#R1">1</a> 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 trials<a href="http://content.nejm.org/cgi/content/full/359/11/1092#R2">2</a> and active surveillance of insurance databases.<a href="http://content.nejm.org/cgi/content/full/359/11/1092#R3">3</a> Meanwhile, the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (ClinicalTrials.gov number, NCT00000620 <a href="http://content.nejm.org/cgi/external_ref?access_num=NCT00000620&link_type=CLINTRIALGOV">[ClinicalTrials.gov]</a> ) 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.<a href="http://content.nejm.org/cgi/content/full/359/11/1092#R4">4</a> 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 <a href="http://content.nejm.org/cgi/external_ref?access_num=NCT00145925&link_type=CLINTRIALGOV">[ClinicalTrials.gov]</a> ).<a href="http://content.nejm.org/cgi/content/full/359/11/1092#R5">5</a> Thus, both macrovascular effects of antidiabetes agents and the optimal glycemic goals, as well as other aspects of combined treatment strategies, remain incompletely understood.<br />Cardiovascular-outcome trials are not required at the time of approval of diabetes drugs (see <a href="http://content.nejm.org/cgi/content/full/359/11/1092#T1">box</a>). 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.<br /> 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.<br />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.<br />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.<br />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.<br />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.<br />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.<br />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.<br />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.<br />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.<br />No potential conflict of interest relevant to this article was reported.<br />Source Information<br />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.<br />References<br /><a name="R1"></a><br />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. <a href="http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=356/24/2457">[Free Full Text]</a><a name="R2"></a><br />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. <a onclick="ISIwin('ISI')" href="http://content.nejm.org/cgi/external_ref?access_num=A1970I068200003&link_type=ISI" target="ISI">[ISI]</a><a name="R3"></a><br />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. <a href="http://content.nejm.org/cgi/external_ref?access_num=10.1002/pds.1443&link_type=DOI">[CrossRef]</a><a onclick="ISIwin('ISI')" href="http://content.nejm.org/cgi/external_ref?access_num=000248553400001&link_type=ISI" target="ISI">[ISI]</a><a onclick="ISIwin('ISI')" href="http://content.nejm.org/cgi/external_ref?access_num=17551989&link_type=MED" target="ISI">[Medline]</a><a name="R4"></a><br />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. <a href="http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=358/24/2545">[Free Full Text]</a><a name="R5"></a><br />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. <a href="http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=358/24/2560">[Free Full Text]</a></div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-71356932004731665422008-09-01T08:31:00.001-03:002008-09-01T08:34:28.640-03:00TIMI-38 Prasugrel em diabéticos<div align="justify"><strong>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</strong> <span style="font-size:78%;">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<br /></span>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.<br />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).<br />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.</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-52628364743379694392008-09-01T04:18:00.001-03:002008-09-01T04:22:37.995-03:003 erros estatísticos<div align="justify"><strong>Three Statistical Errors That Are Totally Trivial but Which Matter a Great Deal</strong><br />Posted 08/18/2008<br />Andrew J. Vickers, PhD<a class="emptytextlink" onclick="showcontent('authordisclosures');">Author Information</a> MEDSCAPE<br />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)."<br />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.<br />Here are the other 3 errors:<br /><strong>P values for baseline differences between randomized groups</strong>. 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.<br /><strong>Inappropriate levels of precision.</strong> 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." <strong>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.</strong> This would require some rather close questioning of the pregnant couple.<br /><strong>Reporting a P value of zero</strong>. 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.<br />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.<br />*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</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-7538389517582618552008-09-01T04:13:00.001-03:002008-09-01T04:16:01.214-03:00Tríplice terapia antiplaquetária aumenta risco na prevenção secundária do AVC<div align="justify"><strong>A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility</strong><br /><span style="font-size:78%;">Nikola Sprigg, Laura J. Gray, Tim England, Mark R. Willmot, Lian Zhao, Gillian M. Sare, Philip M. W. Bath</span><a class="fnoteref" href="http://clinicaltrials.ploshubs.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0002852#cor1"><span style="font-size:78%;">*</span></a><br /><a id="aff1" name="aff1"></a>Abstract<br />Background<br />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.<br />Methodology/Principal Findings<br />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).<br />Conclusions/Significance<br />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.</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-62170381837740829992008-09-01T04:00:00.000-03:002008-09-01T04:01:31.031-03:00Antipsicóticos e risco de AVC<div align="justify">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." </div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-83443844988285708592008-09-01T03:42:00.001-03:002008-09-01T03:57:59.830-03:00Profess: não inferioridade de antiplaquetários<div align="justify"><span style="font-size:85%;">PROFESS Trial Published: Combination Therapy Falls Short of Noninferiority vs Clopidogrel<br />Susan Jeffrey<br /></span><span style="font-size:85%;"> 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.<br />"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.<br />"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.<br />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.<br />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.<br />Factorial Design<br />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.<br />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.<br />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.<br />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<br />PROFESS: Primary Outcome for Comparison of Aspirin Plus Extended-Release Dipyridamole vs Clopidogrel<br />End Point<br />Aspirin + ER-Dipyridamole<br />Clopidogrel<br />Hazard Ratio (95% CI)<br />P<br />Stroke recurrence, n (%)<br />915 (9.0)<br />898 (8.8)<br />1.01 (0.92 – 1.11)<br />.783<br />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.<br />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.<br />PROFESS: Major Hemorrhagic Events<br />Event<br />Aspirin + ER-Dipyridamole<br />Clopidogrel<br />Hazard Ratio (95% CI)<br />Major hemorrhagic events, n (%)<br />419 (4.1)<br />365 (3.6)<br />1.15 (1.00 – 1.32)<br />ICH<br />147 (1.4)<br />103 (1.0)<br />1.42 (1.11 – 1.83)<br />Despite the increase in bleeds, the net risk for recurrent stroke or major hemorrhagic event was similar between the groups.<br />PROFESS: Benefit/Risk Analysis<br />End Point<br />Aspirin + ER-Dipyridamole<br />Clopidogrel<br />Hazard Ratio (95% CI)<br />P<br />Recurrent stroke or major hemorrhagic event, n (%)<br />1194 (11.7)<br />1156 (11.4)<br />1.03 (0.95 – 1.11)<br />.504<br />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.<br />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.<br />"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."<br />Telmisartan vs Placebo<br />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.<br />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.<br />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.<br />PROFESS: Primary and Secondary Outcomes with Telmisartan vs Placebo<br />End Point<br />Telmisartan<br />Placebo<br />Hazard Ratio (95% CI)<br />P<br />Recurrent stroke, n (%)<br />880 (8.7)<br />934 (9.2)<br />0.95 (0.86 – 1.04)<br />.23<br />Major CV events, n (%)<br />1367 (13.5)<br />1463 (14.4)<br />0.94 (0.87 – 1.01)<br />.11<br />New-onset diabetes (%)<br />1.7<br />2.1<br />0.82 (0.65 – 1.04)<br />.10<br />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.<br />"What we need are longer trials, but large trials, with greater blood pressure lowering," Dr. Yusuf concluded.<br />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</span></div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-79664334474251052812008-08-22T23:10:00.001-03:002008-08-22T23:13:08.282-03:00Comentários sobre WENBIT<div align="justify"><strong>Don't End It With WENBIT -- Details Needed on B Vitamins, Stroke, and Cancer</strong> <br /><span style="font-size:85%;">From </span><a href="http://www.theheart.org/" target="_blank" cmimpressionsent="1"><span style="font-size:85%;">Heartwire</span></a><span style="font-size:85%;"> — a professional news service of WebMD<br />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.<br />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.<br />"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.<br />WENBIT results<br />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.<br />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.<br />"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.<br />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.<br />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.<br />WENBIT: Percentage of patients with cardiovascular events<br />End point<br />Folic acid+B12+B6<br />Folic acid+B12<br />B6<br />Placebo<br />Primary end point<br />12.2<br />16.3<br />13.7<br />12.5<br />All-cause death<br />4.5<br />4.9<br />3.6<br />3.9<br />Acute MI<br />7.7<br />9.9<br />7.1<br />7.4<br />Unstable angina<br />2.9<br />3.8<br />3.1<br />3.5<br />Nonfatal thromboembolic stroke<br />1.4<br />2.2<br />2.6<br />2.4<br />Cancer<br />6.0<br />5.1<br />4.9<br />4.0<br />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."<br />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.<br />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</span> Nycomed. The remaining study authors have disclosed no relevant financial relationships.<br />Source<br /><strong><span style="font-size:78%;">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</span></strong></div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-3214737099418685052008-08-22T12:04:00.000-03:002008-08-22T12:06:00.325-03:00Vytorin e câncer: um caso para ser verificado<div align="justify"><a style="COLOR: #000000" name="11bea2f66e5db59c_S1"> FDA investigating link between Vytorin and cancer.</a><br />The <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" onclick="return top.js.OpenExtLink(window,event,this)" href="http://links.mkt1066.com/ctt?kn=20&m=2147204&r=Mjk1MjkxMTYzMwS2&b=0&j=OTc3MDcxMDAS1&mt=1&rt=0" target="_blank" name="11bea2f66e5db59c_feeds_wsjonline_com_~r_wsj_xml">Wall Street Journal</a> (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."<br /> 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," <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" onclick="return top.js.OpenExtLink(window,event,this)" href="http://links.mkt1066.com/ctt?kn=36&m=2147204&r=Mjk1MjkxMTYzMwS2&b=0&j=OTc3MDcxMDAS1&mt=1&rt=0" target="_blank" name="11bea2f66e5db59c_www_bloomberg_com_apps_news_pi"><br />Bloomberg</a> (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."<br /> The FDA "said patients should not stop taking Vytorin because the evidence of a cancer link is unclear," according to the <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" onclick="return top.js.OpenExtLink(window,event,this)" href="http://links.mkt1066.com/ctt?kn=23&m=2147204&r=Mjk1MjkxMTYzMwS2&b=0&j=OTc3MDcxMDAS1&mt=1&rt=0" target="_blank" name="11bea2f66e5db59c_hosted_ap_org_dynamic_stories_">AP</a> (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." <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" onclick="return top.js.OpenExtLink(window,event,this)" href="http://links.mkt1066.com/ctt?kn=70&m=2147204&r=Mjk1MjkxMTYzMwS2&b=0&j=OTc3MDcxMDAS1&mt=1&rt=0" target="_blank" name="11bea2f66e5db59c_www_medpagetoday_com_Cardiolog">MedPage Today</a> (8/21, Peck) and <a style="COLOR: #0e4d96; TEXT-DECORATION: underline" onclick="return top.js.OpenExtLink(window,event,this)" href="http://links.mkt1066.com/ctt?kn=79&m=2147204&r=Mjk1MjkxMTYzMwS2&b=0&j=OTc3MDcxMDAS1&mt=1&rt=0" target="_blank" name="11bea2f66e5db59c_www_webmd_com_cholesterol-mana"><br />WebMD</a> (8/21, DeNoon) also covered the story. </div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-50908134148600047512008-08-20T14:20:00.003-03:002008-08-20T14:27:02.358-03:00Surrogate End-points: ENHANCE<div align="justify"><a href="http://4.bp.blogspot.com/_RxyqpEvyd6k/SKxSlZPY6GI/AAAAAAAAAFY/LYKwiVJQDHA/s1600-h/statin.bmp"><img id="BLOGGER_PHOTO_ID_5236651269109114978" style="FLOAT: left; MARGIN: 0px 10px 10px 0px; CURSOR: hand" alt="" src="http://4.bp.blogspot.com/_RxyqpEvyd6k/SKxSlZPY6GI/AAAAAAAAAFY/LYKwiVJQDHA/s400/statin.bmp" border="0" /></a> <strong>Clinical Trials and Surrogate End Points: Lessons From the ENHANCE Trial</strong><br />Posted 08/12/2008<br />John Alan Farmer, MD<a class="emptytextlink" onclick="showcontent('authordisclosures');">Author </a><br />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]<br />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.<br /><a href="http://images.medscape.com/images/577/927/art-flp577927.fig1.gif" target="Figure" cmimpressionsent="1" s_oidt="0" s_oid="http://images.medscape.com/images/577/927/art-flp577927.fig1.gif"></a></div><div align="justify">Secondary prevention trials and LDL reduction. <br />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.<br />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.<br />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?<br />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.<br />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.<br />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.<br />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.<br />Additionally, LDL-lowering interventions (fibric acid derivatives, nicotinic acid, bile acid sequestrants, diet and ileal bypass) have all been demonstrated to reduce clinical events.<br />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.<br />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.<br /><br /><a href="http://www.medscape.com/viewarticle/577927_print" cmimpressionsent="1"></a><br /><span style="font-size:78%;">References<br />Rifkind BM: The Lipid Research Clinics Coronary Primary Prevention Trial: results and implications. Monogr. Atheroscler. 13, 74-84 (1985).<br />Frick MH, Elo O, Haapa K et al.: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317(20), 1237-1245 (1987).<br />Shepherd J, Cobbe SM, Ford I et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333(20), 1301-1307 (1995).<br />Downs JR, Clearfield M, Weis S et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279(20), 1615-1622 (1998).<br />Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934), 1383-1389 (1994).<br />Sacks FM, Pfeffer MA, Moye LA et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335(14), 1001-1009 (1996).<br />Nissen SE, Tuzcu EM, Schoenhagen P et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291(9), 1071-1080 (2004).<br />Kastelein JJ, Akdim F, Stroes ES et al.: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358(14), 1431-1443 (2008).<br />Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am. J. Cardiol. 80(1), 106-107 (1997).<br />Altmann SW, Davis HR Jr, Zhu LJ et al.: Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 303(5661), 1201-1204 (2004).<br />Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357(9256), 577-581 (2001).<br />Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J. Am. Coll. Cardiol. 49(21), 2129-2138 (2007).<br />Bots ML, Baldassarre D, Simon A et al.: Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations? Eur. Heart J. 28(4), 398-406 (2007).<br />Zhao XQ, Yuan C, Hatsukami TS et al.: Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler. Thromb. Vasc. Biol. 21(10), 1623-1629 (2001).<br />During A, Dawson HD, Harrison EH: Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J. Nutr. 135(10), 2305-2312 (2005).<br />Greenland P, Lloyd-Jones D: Critical lessons from the ENHANCE trial. JAMA 299(8), 953-955 (2008).<br /></span>[</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-63256682796549816352008-08-19T19:39:00.003-03:002008-08-19T19:43:01.693-03:00Folato, B-6 e B-12 como prevenção secundária<div align="justify"><strong>Mortality and Cardiovascular Events in Patients Treated With Homocysteine-Lowering B Vitamins After Coronary Angiography<br />A Randomized Controlled Trial</strong><br /><a class="authstring" href="http://jama.ama-assn.org/cgi/content/full/300/7/795#AUTHINFO"><span style="font-size:78%;">Marta Ebbing, MD; Øyvind Bleie, MD, PhD; Per Magne Ueland, MD, PhD; Jan Erik Nordrehaug, MD, PhD; Dennis W. Nilsen, MD, PhD; Stein Emil Vollset, MD, DrPH; Helga Refsum, MD, PhD; Eva Kristine Ringdal Pedersen, MD; Ottar Nygård, MD, PhD </span></a><br /><strong>JAMA. 2008;300(7):795-804.<br /></strong><a name="ABS"></a>ABSTRACT<br />Context Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B12 can lower plasma total homocysteine levels.<br />Objective To assess the effect of treatment with folic acid and vitamin B12 and the effect of treatment with vitamin B6 as secondary prevention in patients with coronary artery disease or aortic valve stenosis.<br />Design, Setting, and Participants Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes.<br />Interventions Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B12, 0.4 mg, plus vitamin B6, 40 mg (n = 772); folic acid plus vitamin B12 (n = 772); vitamin B6 alone (n = 772); or placebo (n = 780).<br />Main Outcome Measures The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke.<br />Results Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B12. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B12 vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B6 vs 222 (14.3%) not receiving vitamin B6 (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28).<br />Conclusions This trial did not find an effect of treatment with folic acid/vitamin B12 or vitamin B6 on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-22967971503331428712008-08-16T00:54:00.001-03:002008-08-16T00:56:45.442-03:00COURAGE: comentários Medscape<div align="justify"><strong>COURAGE Quality-of-Life Analysis: Slim Early Gains With PCI Soon Disappear<br /></strong>News Author: Steve StilesCME Author: Charles Vega, MD From <a href="http://www.theheart.org/" target="_blank" cmimpressionsent="1">Heartwire</a> — a professional news service of WebMD<br />August 14, 2008 — The results of their quality-of-life (QoL) analysis from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [1] are consistent with the message from its primary outcomes [2] and other secondary results, conclude researchers. That message: Percutaneous coronary intervention (PCI) can often be deferred in patients with stable coronary artery disease (CAD) and significant coronary lesions without adding risk while optimal medical therapy (OMT) is given a chance to work, and it can be considered later if the patient still develops significant symptoms, according to the group.<br />In the trial's QoL analysis, published in the August 14, 2008 issue of the New England Journal of Medicine, OMT either with or without routine early PCI rapidly improved the patients' Seattle Angina Questionnaire (SAQ) scores for physical limitation, angina frequency, overall QoL, and other outcome domains.<br />The gains with routine PCI were significantly greater than those for OMT-only throughout the first one to two years of follow-up. But the PCI advantages had dissipated by three years, when no significant differences in QoL scores were seen between the two treatment strategies.<br />The new report does little to settle controversies ignited when the COURAGE primary outcome — similar composite rates of mortality or myocardial infarction (MI) over four to five years for the routine-PCI and OMT-only groups — became public last year. As extensively reported by heartwire, proponents of early routine intervention have questioned the quality of PCI in COURAGE, the relevance of the trial's exceptionally good medical therapy, its statistical power for prespecified end points, other ways it was designed and executed, the authors' interpretation of the data, and their conclusions; but both detractors and defenders of the trial abound.<br />No additional risk from deferring PCI<br />According to the QoL report's lead author, Dr William S Weintraub (Christiana Care Health System, Newark, DE), the new analysis is consistent with the trial's primary-outcomes message and the results of its "nuclear substudy" [3], which provided objective evidence that the early PCI strategy was better than first-line OMT at relieving myocardial ischemia. COURAGE, he told heartwire, shows that there is some relief of angina with routine early PCI and that about a third of OMT-only patients will cross over to invasive management. "But lots of patients get better without PCI. So it doesn't mean we shouldn't do PCI, it means that people will not be put at additional risk if PCI is deferred to see [whether] they get better with just medical therapy."<br />If the patient reports debilitating symptoms on OMT, Weintraub added, "it's reasonable" to go right to PCI. One finding of the study, he said, is that the QoL benefits of PCI were proportional to the severity of angina.<br />Weintraub had presented a preliminary version of the QoL subanalysis at the American College of Cardiology (ACC) 2007 Scientific Sessions, the meeting at which the trial's primary results were also first formally reported. Both analyses were covered at the time by heartwire.<br />Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), who has defended COURAGE in the literature [4], said to heartwire that "the most remarkable observation from COURAGE is the stellar performance of optimal medical therapy, which not only affected hard outcomes, but more impressively affected outcomes for which PCI clearly was thought to have an advantage, which is relief of angina and ischemia."<br />Although PCI did show significant QoL advantages during the first two years, there is a "disconnect between statistical significance and clinical importance," Kaul said. "While the difference in health status and anginal frequency in COURAGE is unequivocally significant in favor of PCI plus OMT, it is likely too small to be judged as being clinically important."<br />He continued, "if OMT is just as good and doesn't have the drawbacks of being invasive and associated with some periprocedural complications and added cost, then it stands to reason that the initial treatment strategy should then be optimal medical therapy, failing which PCI can be considered."<br />Angina frequency: Mean SAQ scores* by randomization group in COURAGE<br />Follow-up time, mo<br />PCI + OMT<br />OMT<br />p<br />3<br />85<br />80<br />< 0.001<br />12<br />87<br />84<br />0.003<br />24<br />89<br />86<br />0.002<br />36<br />89<br />88<br />0.37SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy*No significant differences between groups at baseline<br />In an editorial accompanying the QoL analysis [5], Dr Eric D Peterson (Duke Clinical Research Institute, Durham, NC) and Dr John S Rumsfeld (University of Colorado Denver Health Sciences Center) also questioned the clinical importance of PCI's early edge. "Depending on the domain evaluated," they write, "the health-status advantages associated with PCI persisted for six to 24 months. However, although the benefits were significant, the comparative differences were small, leaving open the question of whether a PCI-first strategy is justified."<br />As most patients in the OMT-only group showed symptomatic improvement within three months while 21% crossed over to PCI, observe Peterson and Rumsfeld, "a very reasonable take-home message from the COURAGE trial is to pursue optimal medical therapy initially and if this is ineffective, turn to PCI."<br />But interpretations of the QoL analysis vary, as they did for the trial's primary outcomes. The QoL data, Dr Bonnie Weiner (Worcester Medical Center, MA) told heartwire, "clearly shows the symptomatic benefit and the quality-of-life benefit for PCI, and I think that's what the interventional community has been saying all along. I think that actually it's a positive trial from that perspective. . . . I think it reaffirms that patients with more frequent and more severe angina do better with PCI than those with little or no angina. I think that's always been the case, and I don't think any of us have suggested otherwise." Weiner is the immediate past-president of the Society for Cardiovascular Angiography and Interventions.<br />Stepping back a bit . . .<br />COURAGE had randomized 2287 patients with stable CAD, at least one angiographically significant coronary stenosis, and inducible ischemia to either OMT plus PCI or OMT alone at centers in the US and Canada. Stents were used in the overwhelming majority of PCI cases, and they were bare-metal stents in all but a handful. OMT consisted of agents typical of today: nitrates, beta blockers, calcium-channel blockers, statins, and ACE inhibitors or angiotensin-receptor blockers.<br />With 1149 patients assigned to early PCI, the 1138 randomized to OMT-only went to revascularization if their angina failed to respond "or when there was objective evidence of worsening ischemia on noninvasive testing, at the discretion of the patient's physician," the primary report notes [2].<br />The groups didn't differ significantly in the primary end point of death or MI over a median follow-up of 4.6 years; it was 19.0% for early PCI and 18.5% for first-line OMT (p=0.62).<br />In the trial's 313-patient nuclear imaging substudy [3], the PCI-based approach significantly reduced the total burden of ischemia as judged by stress-single photon emission computed tomography (SPECT) myocardial perfusion imaging. The difference was most profound among patients initially with moderate-to-severe ischemia.<br />Quality of life: Mean SAQ scores* by randomization group in COURAGE<br />Follow-up time, mo<br />PCI + OMT<br />OMT<br />p<br />3<br />73<br />68<br />< 0.001<br />12<br />76<br />73<br />0.008<br />24<br />77<br />76<br />0.10<br />36<br />79<br />77<br />0.32SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy*No significant differences between groups at baseline<br />In the current analysis, SAQ scores for the two groups were similar at baseline for all domains and improved significantly by one to three months (p<0.001 for all improvements), write Weintraub et al. "This finding with respect to the benefit of OMT alone shows that PCI is not always essential for the relief of symptoms in patients with stable angina."<br />That observation also intrigued the editorialists. "A remarkable finding from the COURAGE study was the rapidity of improvement in health status in both treatment groups. This should serve as encouraging news to patients with coronary disease," they write.<br />"With contemporary treatment, the majority of patients had substantial improvements in health status that were sustained for several years. At the same time, the rapid improvement with optimal medical therapy alone suggests that antianginal medications are underused in practice."<br />According to Weintraub et al, "Scores were higher in the PCI group than in the medical-therapy group for six to 24 months, depending on the domain. By 36 months, the addition of PCI to optimal medical therapy no longer provided a significant advantage for any domain."<br />That eventual QoL parity between COURAGE groups also has more than one interpretation. While some see it as evidence for only a slim practical difference between the strategies, if any, others point to PCI's early advantage as fundamental to the study's message.<br />PCI's performance in COURAGE was attenuated because DES were only rarely used, observed Weiner. "But for two years or more, the PCI patients felt better, had fewer symptoms, and had a better quality of life," she said. "I do think that's a significant finding."<br />"Bad PCI and unrealistically good medicine"<br />PCI didn't surpass OMT more decisively because the trial used "bad PCI and unrealistically good medicine," Dr Dean J Kereiakes (Christ Hospital Heart and Vascular Center, Cincinnati, OH), coauthor of a published critique of the trial's methods [6], told heartwire.<br />Physical limitation: Mean SAQ scores* by randomization group in COURAGE<br />Follow-up time, mo<br />PCI + OMT<br />OMT<br />p<br />3<br />76<br />72<br />0.004<br />12<br />75<br />73<br />0.21<br />24<br />74<br />72<br />0.16<br />36<br />74<br />74<br />0.68SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy*No significant differences between groups at baseline<br />"I'm amazed PCI as performed in this trial maintained superiority through two years, because of the extremely high frequency of bare-metal stents, high frequency of standard balloon angioplasty, and the incomplete revascularization in the PCI cohort," Kereiakes said.<br />According to the trial's primary report, "complete revascularization was performed as clinically appropriate." But it also notes that 69% and 70% of routine-PCI and OMT-only patients, respectively, had two- or three-vessel disease, whereas only 41% of routine-PCI patients received more than one stent [2]. Only 31 patients received DES, which for most of the study had yet to become available, the report notes.<br />"Think of what could have been achieved if more complete PCI had been performed, with optimal technology — that is, with drug-eluting stents. You would have had a more durable benefit of PCI," Kereiakes said.<br />Excellent medical therapy and a high level of compliance within the confines of the clinical trial also narrowed the outcomes gap between the two patient groups, Kereiakes said. "The level of medication and even the goals achieved, as far as blood-pressure control, cholesterol levels, etc, were truly remarkable in this trial. It's admirable, I think it's inspirational, but it's unrealistic."<br />In the eye of the beholder<br />He added, "Patients with objective evidence of ischemia, absolutely, if feasible, should have PCI plus OMT, unless there are mitigating circumstances." PCI wouldn't be required, he said, if medication completely controls both symptoms and objectively documented ischemia, whether symptomatic or silent.<br />"These data contribute to my enthusiasm for doing PCI better than was done in this trial," Kereiakes said. "Still giving optimal medications to the extent that they're tolerated and the patients are compliant, I have no doubt that a strategy of complete revascularization with optimal technologies would provide a significantly greater gap than was demonstrated to two years in this trial and would extend that benefit beyond two years."<br />On the latter point, Weiner seemed to agree. If recurrent symptoms after PCI are often due to restenosis and DES can "virtually eliminate" restenosis — both ideas are borne out by the data — and then if DES are used in COURAGE-like patients, "it's not unreasonable to think that the separation between the two groups would be wider, and it would be maintained for a longer period of time," she said.<br />More conservative about when to perform PCI in COURAGE-like patients, Kaul outlined a scenario he thinks might indicate invasive management. "If on objective assessment you demonstrate a substantial degree of myocardial ischemia in association with reduced LV [left ventricular] systolic function, that would be a case where I could justify an initial PCI strategy," he said.<br />"I would say, high-risk anatomy and a high-risk functional stress test — a large amount of myocardial ischemia and compromised LV function — those would be reasons why I would offer PCI over medical therapy [only]."<br />Editorialists Peterson and Rumsfeld emphasize that OMT and PCI aren't actually competitors. "The COURAGE trial redefines the contemporary roles of optimal medical therapy and PCI in the management of patients with stable angina. Rather than one victor, COURAGE demonstrates that both treatment strategies can have a profoundly positive effect on patients' health status and suggests complementary roles — optimal medical therapy as first-line therapy, with PCI reserved for patients who do not have a response or who have severe baseline symptoms."<br />Dr. Weintraub has received consulting fees from sanofi-aventis, GlaxoSmithKline, Indigo Pharmaceuticals, and CV Therapeutics and grant support from sanofi-aventis, AstraZeneca, Otsuka, and Bristol-Myers Squib; disclosures for the other COURAGE coauthors and for the 2 editorialists are listed in the original article. Drs. Kaul and Weiner have disclosed no relevant financial relationships. Dr. Kereiakes has disclosed various financial relationships with Abbott/Bioabsorbable Vascular Solutions, Amylin Pharmaceuticals, Cordis/Johnson & Johnson, Boston Scientific, Medtronic, Daiichi Sanyko, Devax, Eli Lilly, and Medpace.<br />Sources<br />Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359:677-687. <a href="http://content.nejm.org/cgi/content/short/359/7/677" target="_blank" cmimpressionsent="1">http://content.nejm.org/cgi/content/short/359/7/677</a><br />Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-16.<br />Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117:1283-1291. PMID: 18268144.<br />Diamond GA, Kaul S. COURAGE under fire. On the management of stable coronary disease. J Am Coll Cardiol. 2007;50:1604-1609. DOI:10.1016/j.jacc.2007.08.010.<br />Peterson ED, Rumsfeld JS. Finding the courage to reconsider medical therapy for stable angina. <a name="bib_1"></a>N Engl J Med. 2008;359:751-753. <a href="http://content.nejm.org/cgi/content/short/359/7/751" target="_blank" cmimpressionsent="1">http://content.nejm.org/cgi/content/short/359/7/751</a><br />Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and consequences of the COURAGE trial. J Am Coll Cardiol. 2007;50:1598-1603. DOI:10.1016/j.jacc.2007.07.063.<br />The complete contents of <a href="http://www.theheart.org/" target="_blank" cmimpressionsent="1">Heartwire</a>, a professional news service of WebMD, can be found at <a href="http://www.theheart.org/" target="_blank" cmimpressionsent="1">www.theheart.org</a>, a Web site for cardiovascular healthcare professionals.<br />Clinical Context<br />The COURAGE trial previously demonstrated that PCI may not improve cardiovascular or mortality outcomes in patients with stable angina and coronary artery disease. In this trial, patients were randomly assigned to undergo PCI plus OMT vs OMT alone. The main result of this trial, which was published in the April 12, 2007, issue of the New England Journal of Medicine, was that there were no significant differences between the group undergoing PCI plus medical therapy and the group that received medical therapy alone in the composite outcome of death, myocardial infarction, and stroke. In addition, rates of hospitalization for acute coronary syndrome and myocardial infarction were similar between treatment groups.<br />QoL is another important outcome for patients with coronary artery disease. The current report from the COURAGE trial examines QoL across multiple domains among randomized groups.<br />Study Highlights<br />Patients eligible for study participation had stenosis of at least 70% in at least 1 epicardial coronary artery or stenosis of at least 80% in 1 coronary artery plus classic angina symptoms.<br />Participants were randomly assigned to receive PCI plus OMT or OMT alone. Medical therapy conformed to standard best treatment for secondary prevention of coronary events.<br />The main outcomes of the study were the 19-item SAQ along with the Research and Development 36-Item Health Survey. These questionnaires were completed at baseline; at 1, 3, 6, and 12 months; and then annually thereafter. Both surveys use a scale of 0 to 100, with a higher score indicating better QoL.<br />2287 patients underwent randomization. The median follow-up period was 4.6 years.<br />88% of participants were experiencing angina at the time of baseline testing. However, the percentage of subjects with angina improved in both randomization groups after 1 month and continued to improve thereafter.<br />PCI plus OMT was superior to OMT alone in the percentage of angina-free patients at 24 months but not at 36 months.<br />The mean baseline scores on the SAQ were 66 for physical limitation, 54 for angina stability, 69 for angina frequency, 87 for treatment satisfaction, and 51 for QoL.<br />At 3 months, all of these values were superior in the group undergoing PCI plus OMT vs the group receiving OMT alone (76 vs 72 for physical limitations, 77 vs 73 for angina stability, 85 vs 80 for angina frequency, 92 vs 90 for treatment satisfaction, and 73 vs 68 for QoL, respectively).<br />Participants with more severe angina at baseline were particularly more likely to benefit from PCI plus OMT vs OMT alone.<br />PCI conferred an incremental benefit on QoL from 6 to 24 months. However, this benefit was not significant at 36 months.<br />Responses to the Research and Development 36-Item Health Survey improved in both groups between 1 and 3 months, although the group undergoing PCI plus OMT improved to a larger degree than the group receiving OMT alone at 3 months. This difference between groups in this outcome disappeared by 12 months.<br />The authors conclude that 12.5 patients would need to be treated with PCI in addition to OMT to achieve 1 additional significant improvement in QoL.<br />Pearls for Practice<br />A previous report from the COURAGE trial demonstrated no significant difference between PCI plus OMT and OMT alone in the composite outcome of death, myocardial infarction, and stroke. In addition, rates of hospitalization for acute coronary syndrome and myocardial infarction were similar between treatment groups.<br />In the current study of the COURAGE trial, PCI in addition to OMT improved QoL through 24 but not 36 months. Patients with more severe angina were likely to benefit from the addition of PCI to OMT</div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-45235220057242622932008-08-14T00:07:00.001-03:002008-08-14T00:09:31.304-03:00Tibolona na pós-menopausa<div align="justify"><strong>The Effects of Tibolone in Older Postmenopausal Women</strong><br /><span style="font-size:78%;">Steven R. Cummings, M.D., Bruce Ettinger, M.D., Pierre D. Delmas, M.D., Ph.D., Peter Kenemans, M.D., Ph.D., Victoria Stathopoulos, Ph.D., Pierre Verweij, Ph.D., Mirjam Mol-Arts, M.D., Lenus Kloosterboer, Ph.D., Lori Mosca, M.D., Ph.D., M.P.H., Claus Christiansen, M.D., John Bilezikian, M.D., Eduardo Mario Kerzberg, M.D., Susan Johnson, M.D., Jose Zanchetta, M.D., Diederich E. Grobbee, M.D., Ph.D., Wilfried Seifert, Ph.D., Richard Eastell, M.D., for the LIFT Trial Investigators</span><br /><br /><a href="https://secure.nejm.org/campaigns/Register/REGONJEJ0607/REGONJEJ0607.aspx?promo=ONFLNR28&cpc=REGONJEJ0607"></a>ABSTRACT<br />Background Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain.<br />Methods In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of –2.5 or less at the hip or spine or a T score of –2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels.<br />Results During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.<br />Conclusions Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. </div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0tag:blogger.com,1999:blog-1006510777259010136.post-36886357086021249852008-08-13T23:58:00.001-03:002008-08-14T00:01:53.272-03:00Anticoagulação na angioplastia para angina<div align="justify"><strong>Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention<br /></strong><span style="font-size:78%;">Adnan Kastrati, M.D., Franz-Josef Neumann, M.D., Julinda Mehilli, M.D., Robert A. Byrne, M.B., M.R.C.P.I., Raisuke Iijima, M.D., Heinz Joachim Büttner, M.D., Ahmed A. Khattab, M.D., Stefanie Schulz, M.D., James C. Blankenship, M.D., Jürgen Pache, M.D., Jan Minners, M.D., Melchior Seyfarth, M.D., Isolde Graf, Pharm.D., Kimberly A. Skelding, M.D., Josef Dirschinger, M.D., Gert Richardt, M.D., Peter B. Berger, M.D., Albert Schömig, M.D., for the ISAR-REACT 3 Trial Investigators</span><br />ABSTRACT<br />Background Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown.<br />Methods We enrolled 4570 patients with stable or unstable angina (with normal levels of troponin T and creatine kinase MB) who were undergoing PCI after pretreatment with a 600-mg dose of clopidogrel at least 2 hours before the procedure; 2289 patients were randomly assigned in a double-blind manner to receive bivalirudin, and 2281 to receive unfractionated heparin. The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization.<br />Results The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P=0.57). The secondary end point occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P=0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P=0.008).<br />Conclusions In patients with stable and unstable angina who underwent PCI after pretreatment with clopidogrel, bivalirudin did not provide a net clinical benefit (i.e., it did not reduce the incidence of the composite end point of death, myocardial infarction, urgent target-vessel revascularization, or major bleeding) as compared with unfractionated heparin, but it did significantly reduce the incidence of major bleeding. (ClinicalTrials.gov number, NCT00262054 <a href="http://content.nejm.org/cgi/external_ref?access_num=NCT00262054&link_type=CLINTRIALGOV">[ClinicalTrials.gov]</a> .)<br /></div>Anonymoushttp://www.blogger.com/profile/00246144050660663066noreply@blogger.com0