NHLBI досрочно прекратило один из видов лечения в исследовании ACCORD

[LupusDoc]

Организаторы крупного клинического испытания ACCORD (Action to Control Cardiovascular Risk in Diabetes) [Ссылки доступны только зарегистрированным пользователям ] у больным СД 2 типа на 18 месяцев раньше срока прекратили лечение по программе интенсифицированного контроля гликемии в связи с превышением смертности в этой группе по сравнению с группой обычного контроля диабета [Ссылки доступны только зарегистрированным пользователям ].
В группе интенсифицированного контроля гликемии ставилась цель снижения HbA1C ниже 6% и у половины удалось снизить HbA1C ниже 6.4%. В группе обычного контроля целью лечения являлись уровни HbA1C 7.0 - 7.9% (половина достигла уровня ниже 7.5%). Общее число участников РКИ ACCORD - 10251, продолжительность исследования к настоящему моменту почти 4 года, планируемая дата заверения РКИ - середина лета 2009 года. Превышение смертности в группе интенсифицированного контроля составило 3 на 1000 человеко/лет.

[Anna_Shvedova]

Раннее и агрессивное вмешательство у больных СД 2 типа с микроальбуминурией приводит к уменьшению общей смертности на 20%, показывают результаты датского исследования Steno-2.

February 8, 2008 — A new Danish study, Steno-2, has shown that in high-risk type 2 diabetes patients, early intensive intervention with multiple drug combinations and behavior modification leads to reduced rates of death and cardiovascular disorders [1]. Dr Peter Gaede (Steno Diabetes Center, Copenhagen, Denmark) and colleagues report their findings in the February 7, 2008 issue of the New England Journal of Medicine.

"The most impressive finding is the 20% absolute risk reduction in the primary end point — all-cause mortality — after a total of 13.3 years of follow-up. Similarly, the absolute risk reduction for cardiovascular death was 13.0%. We show these risk reductions in high-risk type 2 diabetes patients — defined by the presence of microalbuminuria — who were originally treated in the intensive arm of our study for close to eight years," principal investigator Dr Oluf Pedersen (Steno Diabetes Center) told heartwire. He added that this is the first time that such an absolute risk reduction has been shown in any high-risk group of diabetics.

The results of Steno-2 at first glance appear to be in direct contrast to those of a National Heart, Lung, and Blood Institute (NHLBI) study, Action to Control Cardiovascular Risk in Diabetes (ACCORD), in which the blood-glucose-lowering arm has just been prematurely halted, as reported by heartwire. This was due to a higher mortality in patients in the intensive glucose-lowering arm compared with patients in the standard arm.

But Pedersen is keen to point out that the study populations of the two trials should not be confused, as "there is a huge difference between Steno-2 and ACCORD." Patients in Steno-2 were younger, had had diabetes on average six years, and were deemed high risk by the presence of microalbuminuria rather than having heart disease or two known risk factors for heart disease, as in ACCORD (just 25% of Steno-2 patients had known cardiovascular disease on entry). Also, because of treatment resistance, only 18% of patients in Steno-2 achieved the target glycated hemoglobin (HbA1c) level of below 6.5%, he notes. "The impact on mortality and micro- and macroangiopathy in Steno-2 is likely related to the early and additive effects of treating dyslipidemia, hypertension, hyperglycemia, and platelet aggregation in a relatively intensive and structured way."

[Melnichenko]

Как всегда, проблема в том, кого набирали и как агрессивно снижали,,Трудно обеспечить бессмертие второму типу

[KMN]

Продолжение темы с сайта theheart.org, о использовании сурогатных конечных точек в общем и об этом исследовании в частности. Статья из Washington Post написана, как бы для дилетантов.

Surrogate end points in the media firing line

February 19, 2008 Sue Hughes

Washington DC - Following the recent findings from ACCORD and ENHANCE, the questions of whether too many drugs are being used to treat cardiovascular disease and diabetes and whether new drugs are being adequately tested before being allowed on the market are addressed in an article in the February 19, 2008 issue of the Washington Post.

Journalist Rob Stein quotes Dr Harlan Krumholz (Yale University, New Haven, CT) as saying: "We definitely need to pause and reassess our assumptions about what is best for patients. . . . Clearly we have more to learn," while Dr Steven Nissen (Cleveland Clinic, OH) is reported as saying: "There is a wake-up call in all of this. . . . We can't rely on assumptions. We don't always understand the biology of how drugs work as well as we think."

But Dr Sidney Smith (University of North Carolina, Chapel Hill) warns against overreacting to a handful of studies and says that, if anything, too few patients are receiving recommended care. "We have to be careful we don't get swept up by these swings and go too far one way or the other," he says in the article.

Stein outlines the three latest studies to throw into question the idea of using surrogate end points to evaluate drugs—the failure of torcetrapib, which raised HDL cholesterol but also increased mortality; the ENHANCE study, showing no reduction in atherosclerosis progression with ezetimibe despite its LDL lowering; and the shock results of ACCORD, in which a very intensive strategy to lower blood-sugar levels in diabetics was associated with increased mortality. "I don't think you can leave these episodes and not shake your head and say, 'Wow, we really don't know as much as we think we do,' " Krumholz is reported as saying. Dr Nortin Hadler (University of North Carolina) adds: "There are a lot of things we do in this country where we treat these surrogate measures with very little evidence that we are actually treating the patient."

Nissen suggests in the article that drugs could be approved on the basis of surrogate end points but only with the proviso that a clinical-outcome trial is conducted. But the FDA is defending the approval of drugs based on surrogate end points. Robert Temple (FDA's Center for Drug Evaluation and Research) told the newspaper: "Some people don't respond adequately to available therapy. . . . You have to make a judgment about whether you want to have a way of treating that now or you want to wait five years, 10 years, who knows? That's a judgment that has to be made."

Others lay the blame with the drug companies. Dr John Abramson (Harvard Medical School, Boston, MA), who is author of the book Overdosed America, comments: "What's going on here is our research enterprise is almost completely controlled by the pharmaceutical industry. . . . It's their job to create a need for their products. Their job is not to maximize public health." Dr Howard Brody (University of Texas Medical Branch at Galveston) adds: "People are making a ton of money by selling the drugs and the monitoring equipment. . . . It distracts our patients from what really matters more, which may be getting more exercise or making lifestyle changes that ultimately may be more beneficial than obsessing about their blood sugar or playing with their little monitor device."

And some believe doctors themselves add to the problem by overprescribing drugs. Dr Mark Ebell (deputy editor of American Family Physician) is quoted as saying: "It feeds on the American psyche of 'Just don't stand there, do something.' . . . We want to do everything possible. Sometimes pushing too hard to make a number look better can have unexpected collateral effects that do harm a patient."

But the Post also reports lipid expert Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) as saying that the link between cholesterol and heart disease is "the most established fact in all of medicine . . . the more you lower LDL cholesterol, the more you lower the risk." But Grundy adds: "Drugs can be great, but they can have side effects. . . . If you start piling on one drug after another, you can get into trouble."

[Ссылки доступны только зарегистрированным пользователям ]

[Melnichenko]

С ACCORD не так однозначно

При 2 типе человечество долго не принимало идею близконормальных сахаров, довольствуясь безжалобной жизнью ( аналог терапевтической идеи "рабочего давления" ) но UKPDS доказало, что гликогемоглобин 7,5 % у этих больных дает основания расчитывать на снижение микрососудистых осложнений ( напомню, что при 2 типе НА момент диагностики у половины микро- или макрососудистые осложения ), но НЕ снижает статистически значимо ( прошло различие в 16% при p ( если не изменяет память ) 0,052 ( sic!) макрососудистых осложнений

Идей было две: диабет 2 типа это еще и гиперлипидемия и артериальная гипертензия, и может, еще чуть - чуть снизить сахар? ( у здорового HbA1c будет меньше 6 % - не будем углубляться в дебри методик, тут свои заморочки)

Словом, какое -то время сосредоточились на лечения по всем фронтам ( нормогликемия + целевое АД с целевым гликогемоглобином до 7% )- даже дисциплинированые скандинавы получили 10 %( тоже могу соврать, но не сильно) достижения всех трех целевых уровней ( STENO) причем цены немалые на эту коррекцию ..

Тогда возник вновь вопрос об эффективном и экономичном управлении диабетом : уже сейчас в мире 260 млн больных диабетом ( это больше, чем полторы России) , а к 2025 году будет 300 млн ( или 360 ) - не хило..

Итого, NIH начала исследование для уточнения стратегии управления диабетом 2 типа ( это не единственное, и два других из других центров и с другими , но сходными дизайнами идут- ADVANCE, нпрм)

Больных было включено 10251 человек

Были две группы - с принятым на сегодня + практически приемлемым ( 7,0 -7,9 % ) целевым гликогемоглобином и " как у здоровых "- меньше 6,0%
Исследование многоцентровое / рандомизация начато в 2001 году, помимо контроля гликемии , включали еще и статины только или фибраты со статинами и АД сист ( ниже 120 или ниже 140 как цель)
Cпустя 4 года ветвь гликогемоглобина "как у здоровых" была закрыта : больше смертей -257/ на 5128 участников при 203/5123 на стандартном на сегодня гликогемоглобине

Анализ данных на сегодня не выявил причин повышения смертности - это не гипогликемии и не росиглитазон ( два основных потенциальных обвиняемых на вскидку )

Любопытно, что в группе жесткого контроля оказалось на 10 % меньше ( ТАК !!! ) нефатальных кардиальных исходов

Информация полная ( включая анализ гиполипидемической и гипотензивной терапии) будет получена к концу 2009 года, так что мы пока ответа не знаем - это шутки статистики или какой-то неизвестный нам факт, но эти даные не подрывают сегодняшнюю тактику ведения и не отрицают контроль до 7 % гликогемоглобина ..

[o_udovichenko]

Вот, на Medscape еще интересная информация на этот счет:

ADVANCE Does Not Confirm ACCORD Results
from Heartwire — a professional news service of WebMD

Sue Hughes

February 14, 2008 (Sydney, Australia) - Preliminary findings from the ADVANCE trial provide no evidence that intensive treatment to lower blood-glucose levels in type 2 diabetics increases mortality risk.

The ADVANCE study is similar to the blood-glucose-lowering part of the ACCORD trial, which was stopped last week because of a higher number of deaths in patients allocated to intensive glucose lowering rather than standard treatment.

In a press release released by the ADVANCE group, principal investigator Prof Stephen MacMahon (The George Institute, Sydney, Australia) stated that "Due to the unexpected report from the ACCORD trial, we felt it was in the public interest for us to ask our data monitoring and safety committee to make a statement as to whether the available data from ADVANCE provide any support for the suggestion that intensive blood-glucose lowering may increase mortality."

"Reassured"

ADVANCE management committee chair Prof John Chalmers (The George Institute) commented: "Doctors and patients should feel reassured that the mortality trend reported by the ACCORD study has not been found in the interim results from ADVANCE. However, we need to await more definitive analyses and reports from both studies before drawing final conclusions."

ADVANCE involves 11 140 high-risk patients with type 2 diabetes who were randomized to intensive or standard glucose-lowering treatments. The study is just coming to an end, but the database is still locked and the investigators still blinded while the data are checked and cleaned up, study director Dr Anushka Patel (The George Institute) told heartwire. The database will be unlocked in March and the analysis will begin at that point. She added that the data were now "more than 99% complete and so we are confident that the interim findings communicated here are a reliable guide to the final results."

Twice as much data as in ACCORD

In the press release, data safety and monitoring board (DSMB) chair, Prof Rory Collins (University of Oxford, UK), said the data provided "no confirmation" of the adverse mortality trend reported from the ACCORD study. He also noted that the ADVANCE interim results were based on more than twice as many data and similar levels of glucose control as in ACCORD.
..... продолжение здесь: [Ссылки доступны только зарегистрированным пользователям ]

Всегда, конечно, больше всего боялись вреда для сердечно-сосудистой системы у пожилого пациента от гипогликемий, неизбежных при жестком контроле СД.
Но вот в исследовании DIGAMI [1997] было уменьшение смертности у больных СД, получающих интенсифицированную инсулинотерапию после инфаркта миокарда, несмотря на увеличение частоты гипогликемий.