Drug-Eluting Stent Mortality Meta-Analysis

[Parcell]

Почему ботаников так не любят?
После пары ботанических откликов у меня неожиданное получилась отвратительная репутация (спасибо папедоктору, алексу мэде и проч), с толерантностью у Вас в порядке.
P.S. А если физик - то сразу рвота?

[papadoctor]

С толерантностью и терпением проблем нет, а то бы давно наябедничал бы на Вас модерам! Свою пошатнувшуюся репутацию Вы можете подправить в разделе " Медицинкий юмор и анекдоты...", где за каждый новый анекдот ( который я не знаю) Вы будуте получать мои одобрямсы! В этом разделе общаются врачи, имеющие понятие о чём изначально идёт речь.Успехов в нелёгком ботаническом труде!

[Igor73]

Title: Drug-Eluting Stents: An Ounce of Prevention for a Pound of Flesh?
Author: Sanjay Kaul, M.B.B.S.
Author Disclosure: This author has nothing to disclose.
Author: George A. Diamond, M.D., F.A.C.C.
Author Disclosure:
Date Posted: 10/11/2006

September 14, 2006
FDA is issuing an alert to consumers about an outbreak of E. coli O157:H7…. To date, preliminary epidemiological evidence suggests that bagged fresh spinach may be a possible cause of the [50 cases of illness and one death among millions of potential consumers]…. Based on the current information, FDA advises that consumers not eat bagged fresh spinach at this time.

September 14, 2006
FDA [is] aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES…. [T]he data we currently have do not allow us to fully characterize the mechanism, risks, and incidence of DES thrombosis…. At this time, FDA believes that coronary DES remain safe and effective….

"Drug-eluting stents (DES) have dramatically transformed the landscape of interventional cardiology largely on the basis of empirical evidence showing profound reduction in angiographic and clinical restenosis without any significant increase in adverse events. The justification for the enormous surfeit of DES use (totaling nearly 6 million patients globally to date at a cost of $4-5 billion annually) is founded on the notion that restenosis-although not a major impediment on survival-impacts importantly on quality-of-life, and the need for repeat revascularization. To some extent, our preoccupation with cosmetic angiographic improvement as a surrogate for meaningful clinical benefit has fueled the unbridled enthusiasm for DES, typified by proclamations to the effect that "the Achilles' heel of stenting (restenosis) has finally been put to rest" (sic) (MB Leon, Intervention 2003, Atlanta). But is the reality as stirring as the high-flown rhetoric?"

Restenosis
The clinical benefits of DES relative to target vessel restenosis and target vessel revascularization (TVR) have been overestimated.1 For example, the TVR rates in the control bare-metal stent (BMS) group were nearly 50% higher in the DES trials than that observed in contemporary interventional trials or in “real-world” clinical practice.1,2 This may be a consequence of two factors: 1) the use of thick-strut stents in the former versus thin-strut stents in the latter,1 and 2) protocol-driven angiography in the DES studies, which may have biased the TVR outcomes against BMS.1,2

The inflated benefit observed with DES in clinical trials may not be applicable in routine practice, as exemplified by the results of the BASKET trial (TVR rate of 7.8% at 6 months) where optimal grade thin-strut BMS such as Multi-link Vision (81 μm thick) was used and routine angiography was not performed.3

In addition, the restenosis benefit with DES is attenuated in high-risk patient and lesion cohorts (diabetes, acute coronary syndromes, multivessel disease, arterial bifurcations, left main disease, and other off-label subsets) that were not evaluated in the pivotal trials, but represent >50% of patients undergoing elective stenting in clinical practice.1 For example, the relative risk reduction with respect to TVR is reported to be in the range of 67% in the non-high-risk cohorts of the pivotal studies ( SIRIUS, TAXUS-IV) versus 30% in the higher risk cohorts of others (TAXUS-V).1

Thrombosis
Unlike restenosis, stent thrombosis is a rare but potentially life-threatening complication of coronary stents. In clinical trials, the cumulative incidence of stent thrombosis with DES at 9-12 months has ranged from 0.4% to 0.6%, roughly comparable to the incidence with BMS.1 By contrast, the rate in registries more representative of clinical practice has been reported to be two- to three-fold higher.4 Nearly half of the episodes occurred >30 days (late stent thrombosis) and almost half of these resulted in death.4 The strongest independent predictor of stent thrombosis was premature discontinuation of dual antiplatelet therapy.

These observations were recently replicated in the BASKET LATE trial, which reported a nonsignificant two-fold increase in thrombosis-related events (1.3% vs. 2.6% DES) 12 months after discontinuation of dual antiplatelet therapy (median time = 116 days).5 As a result, some experts have called for extending dual antiplatelet therapy beyond that recommended by treatment guidelines (3 months with sirolimus-eluting stent [SES] and 6 months with paclitaxel-eluting stent).

However, the results of the PREMIER registry, where nearly one in seven discontinued treatment within 30 days of DES (these patients experiencing a nine-fold higher risk of an adverse event), underscore the challenge of adherence with such a strategy.6 Moreover, the long-term use of dual antiplatelet therapy is not without risk, as illustrated by a significant increase in bleeding complications.7

Recent reports have suggested an even higher rate of stent thrombosis associated with more complex stenting procedures.8,9 A recent study, which tracked stent thrombosis rates over 3 years in 8,000-plus patients enrolled in studies in Holland and Switzerland, reported a similar rate of thrombosis of 1.2% at 30 days in the BMS and DES group.10 However, while the stent thrombosis rate waned with time in the former, it continued to occur at a rate of 0.6% per year in the latter (cumulative rate of 2.9% at 3 years), confirming concerns raised earlier in a meta-analysis of 20 trials.11 Further confirmation of late stent thrombosis in DES was provided by the recent announcement by Boston Scientific who reported a small, but statistically significant, 0.5% increase in late stent thrombosis at 4 years with its Taxus stent.12

Thus, these findings highlight the increased risk of late stent thrombosis associated with DES in more complex lesions and patients than evaluated in the initial clinical trials or Food and Drug Administration (FDA)-approved indications, the unacceptably high mortality associated with it, the challenge of continuing long-term antiplatelet therapy, and the danger of early discontinuation of antiplatelet therapy.

Death and Myocardial Infarction
Even though randomized trials have consistently shown reductions in TVR with DES, none of these trials was adequately powered to reliably evaluate relatively infrequent but more relevant clinical endpoints such as death or myocardial infarction (MI).

Recently, pooled data from long-term follow-up of major DES trials presented at the European Society of Cardiology/World Congress of Cardiology meeting in Barcelona revealed significantly increased rates of death or Q-wave MI (presumably due to stent thrombosis), and increased rates of noncardiac death with DES, especially SES (Figure 1). In a separate meta-analysis of 17 randomized trials, treatment with DES was not associated with a significant difference in total mortality at 3 years (odds ratio [OR] 1.00; 95% confidence interval [CI], 0.62-1.60), but was associated with increased noncardiac mortality with SES compared with BMS (OR, 2.04; 95% CI, 1.00-4.15; p < 0.05).13

Although these preliminary estimates are by no means conclusive (they require a more formal evaluation and thorough peer review), they sound a disquieting alarm because they are consistent with the trial-by-trial pattern of findings with respect to death or MI over 18 months to 5 years of follow-up (Figure 1). Even though the differences in death or MI were not statistically significant in any one of the individual trials (due to inadequate power), the number needed to harm (NNH) with DES ranged from 12 to 111 and the probability of harm ranged from 68% to 96% (Figure 1).

Given the projected small difference in outcome, an adequately powered prospective trial to reliably estimate the true excess risk would require the enrollment of 10,000 subjects followed for 5 years (α = 0.05, β = 0.2). Although such a trial would be desirable, it is doubtful that it will ever be done.

Thus, in the absence of a definitive trial, based on the reported estimate of 0.6% excess late stent thrombosis per year, and the attendant case fatality rate of 45%, we nevertheless estimate that using DES in 80% out of 1 million percutaneous coronary intervention cases would translate into 2,160 excess deaths per year attributable to late stent thrombosis in the United States alone (0.006 x 0.45 x 0.80 x 1,000,000)–a risk far worse than that of tainted spinach no matter how profound the reduction in restenosis!

[Igor73]

Implications
Our romance with new technology–DES being only the most recent instance–is entirely understandable. Technological innovation accounts for much of the miracle in modern medicine. It is entirely understandable, then, that: 1) device companies should want to develop new technology and support clinical trials necessary for regulatory approval and marketing so as to profit from the sale of that technology in a capitalistic market; 2) medical investigators should want to perform and publish such studies as a way to advance their careers; 3) insurance companies should want to rely on this information to justify reimbursing hospitals and physicians for utilization of that technology lest they be charged with restricting access to care in return for reducing their costs; and 4) hospitals and physicians should want to employ such state-of-the-art technology, and that patients should demand its use–even before long-term outcome trials confirm the short-term promise of that technology.

Together, all these individually understandable incentives conspire to introduce promising new technology too quickly into the medical marketplace and to encourage its rapid overutilization. It is not at all surprising then that conflicts should exist between clinical practice and its evidentiary support, and that many DES interventions are thereby insufficiently justified.

What are the possible alternative actions based on the new information? Consider the following: 1) Nothing–wait for thorough peer review; 2) expanded educational efforts to physicians and patients (this essay, news stories); 3) American College of Cardiology/American Heart Association or European Society of Cardiology task force to expedite review of information, issue a report, and recommend guidelines; 4) FDA review and resultant labeling changes if warranted (revised approved indications, boxed warning, etc.); 5) a more accurate, timely, and comprehensive postmarket surveillance program; 6) voluntary moratorium on use; or 7) manufacturer voluntary recall.

While the current information does not justify #6 or #7, in our opinion, the responsible action warrants more than #1-3; perhaps #4 and #5. The recent FDA statement that it would convene a public panel in the near future to examine the risk of DES thrombosis is a small step in the right direction.14 However, in the end, regulatory guidelines and warnings can only do so much.

The FDA statement that “coronary DES remain safe and effective when used for the FDA-approved indications” ignores the nearly 80% off-label use of these devices in the “real world.” Although the FDA does not have the mandate to impact medical practice, it should nevertheless leverage its relationships with medical professional societies and device sponsors to collaborate on the development and implementation of new tools and programs that help mitigate unnecessary risk and promulgate best practice standards.

The town-gown conflicts between academics who formulate treatment guidelines and clinicians who apply them in real-world practice are not unique to medicine. They are experienced too by the legal scholars who define judicial rules of evidence and the trial attorneys who seek to bend them, and by the military strategists who set the rules of engagement and the soldiers who must interpret them in the heat of combat. In the current context, it appears that the rules regarding use of DES, while justifiable to combat the knotty problem of restenosis (“an ounce of prevention”), have inadvertently led to the new and even more intractable problem of late stent thrombosis (“a pound of flesh”).
Surely, it is time to refine the use of this innovative technology, so that its benefits outweigh its cost and potential for harm. To this end, we endorse the following recommendations:

Initial DES use in selective patients at high risk for restenosis (for example, smaller diameter vessels or longer lesions where TVR rates generally exceed 15%-20%).
Provisional or bailout DES use in those who present with restenosis following BMS.
Strict avoidance of DES in those unable or unlikely to comply with long-term dual antiplatelet therapy.
For left main disease and multivessel disease, especially diabetics, coronary artery bypass surgery should remain the treatment of choice, until randomized data prove the effectiveness and safety of DES in these conditions.

Our recent DES review closed with the conclusion that:

“...it makes little clinical, economic, or common sense to forsake a therapy that works well for most patients (bare-metal stents) in favor of a costly new therapy (drug-eluting stents) that has no effect on important clinical outcomes but increases the risk for stent thrombosis, a life-threatening complication.1”

Notwithstanding the FDA’s position statement, the latest clinical trial data serve only to reinforce that conclusion. The DES may well have done away with the “Achilles’ heel” of stenting (restenosis), perhaps only to be replaced by the “Damocles’ sword” of stenting (stent thrombosis)!

Editor's Note: With the recent controversy over the long-term outcome for drug-eluting stents, this commentary by Drs. Kaul and Diamond is timely and certain to provoke some discussion.
NOTE: The author´s comments express his or her personal opinions and do not necessarily reflect the official position of the American College of Cardiology.

References
1. Tung R, Kaul S, Diamond GA, Shah PK. Narrative review: drug-eluting stents for the management of restenosis: a critical appraisal of the evidence. Ann Intern Med 2006;144:913-9.
2. Yock A, Isbill JM, King SB 3rd. Bare-metal stent outcomes in an unselected patient population. Clin Cardiol 2006;29:352-6.
3. Kaiser C, Brunner-LaRocca HP, Buser PT, et al. Incremental cost-effectiveness of drug-eluting stents compared with a third-generation bare-metal stent in a real-world setting: randomised Basel Stent Kosten Effektivitäts Trial (BASKET). Lancet 2005;366:921-9.
4. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30.
5. Pfisterer ME, Kaiser CA, Bader F, et al. Late clinical events related to late stent thrombosis after stopping clopidogrel: prospective randomized comparison between drug-eluting versus bare-metal stenting. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract :422-11.
6. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006;113:2803-9.
7. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.
8. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon post-dilation. J Am Coll Cardiol 2005;46:613-20.
9. Rodriguez AE, Mieres J, Fernandez-Pereira C, et al. Coronary stent thrombosis in the current drug-eluting stent era: insights from the ERACI III trial. J Am Coll Cardiol 2006;47:205-7.
10. Drug-Eluting Stent: Long-Term Follow-Up. Presented by P. Wenaweser, European Society of Cardiology Scientific Congress, September 2006.
11. Stent Thrombosis with Drug-Eluting Stent: A Meta-Analysis of 20 Trials. Presented by A. Bavry, AHA Scientific Sessions, November 2005.
12. Westphal SP, Winslow R. Boston Scientific acknowledges risks tied to stent. Wall Street Journal. September 7, 2006.
13. Drug-Eluting Stent Mortality Meta-Analysis. Presented by A.J. Nordmann, European Society of Cardiology Scientific Congress, September 2006.
14. FDA Statement on Coronary Drug-Eluting Stents. September 14, 2006.
[Ссылки доступны только зарегистрированным пользователям ]

[Igor73]

Late Stent Thrombosis: Considerations and Practical Advice for the Use of Drug-Eluting Stents: A Report From the Society for Cardiovascular Angiography and Interventions Drug-eluting Stent Task Force
Catheterization and Cardiovascular Interventions 69:000–000 (2007)
[Ссылки доступны только зарегистрированным пользователям ]

SUMMARY
In light of the observed small increased incidence of very late thrombosis seen after DES implantation we advise the following:
1. Prior to any stent implantation, patients should meet criteria for PCI according to published guidelines.
2. The decision to implant a DES vs. an alternative revascularization
strategy (including bare metal stents or surgical revascularization) must be made on an individual patient basis after consideration of the relative risks and benefits of each therapy.
3. Careful evaluation of the patient with respect to compliance and the risks of long-term dual antiplatelet therapy must be performed prior to implanting
a DES.
4. Careful attention must be paid to stent implantation technique. The use of intravascular ultrasound, screening for calcification, and careful lesion preparation are encouraged.
5. Following DES implantation, dual antiplatelet therapy should be prescribed for no less than 3 months (Cypher) or 6 months (Taxus) for patients meeting
the FDA approved indications. In such patients who are not at high risk for bleeding, we strongly recommend the continuation of dual antiplatelet therapy
for 12 months. Until the issue of very late stent thrombosis is further studied, we recommend that patients at higher risk for stent thrombosis be considered for dual antiplatelet therapy for longer than 12 months after careful review of the risks and benefits.
6. The discontinuation of dual antiplatelet therapy (either transiently or permanently) requires careful consideration of the relative risks of continuation (primarily bleeding and cost) and the potential risks of late stent thrombosis. This decision must be individualized. There are no tested \bridging" strategies.
7. The medical decision making process, risks and benefits of all appropriate therapies, and the need for dual antiplatelet therapy should be discussed with
the patient and documented in the medical record.
8. Patients should be reassured that the implantation of a DES, after careful consideration with their physician, remains a very effective method for the treatment for symptoms associated with the disabling problem of coronary artery disease.

[Igor73]

Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting. However, many patients and healthcare providers prematurely discontinue dual antiplatelet therapy, which reatly increases the risk of stent thrombosis, myocardial infarction, and death. This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent and educating the patient and healthcare providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients with drug-eluting stents. (Circulation. 2007;115:&NA;-.)
[Ссылки доступны только зарегистрированным пользователям ]

Предупреждение против отмены терапии аспирин + плавикс после стентирования как минимум в течение 12 месяцев.

[Igor73]

В последнее время появилось ряд сообщений о важности непрерывного приёма комбинации клопидогрель+аспирин после установки DES. Учитывая большую распространённость стентирования, достаточно актуальной может стать проблема непереносимости/резистентности к клопидогрелю/аспирину. Появились сообщения об аллеригческой реакции на клопидогрель.
В связи с этим:
1. Чем можно заменить клопидогрель в случае непереносимости/резистентности или в случае, когда его необходимо отменить (например, хирургическое вмешательство)? Стоит ли назначать фракционированные гепарины в этом случае?
2. Существуют ли в России лабораторные методы определения резистеннтности к клопидогрелю/аспирину?

[audovichenko]

Сообщение от Igor73

Чем можно заменить клопидогрель в случае непереносимости/резистентности или в случае, когда его необходимо отменить (например, хирургическое вмешательство)?

Существует официальная рекомендация: отмена клопидогреля за 5 суток до вмешательства, затем назначение его вновь.
Непереносимость мне за все время, что мы назначаем клопидогрель (с 1999 года - всем подряд), не встречалась ни разу. И аллергия не встречалась, хотя это даже как-то странно. Обычно пациенты (чаще женщины) жалуются на легкость образования синяков - но мы их убеждаем продолжить лечение .

Стоит ли назначать фракционированные гепарины в этом случае?

Официальной рекомендации, по-моему, нет. Все зависит от того, сколько времени прошло от установки стента. По реальной жизни мы рекомендуем отложить плановую операцию до 6 мес после стентирования, а затем оперировать с последующим возобновлением терапии клопидогрелем после операции. Если же операция экстренная, то мы все-таки назначаем гепарины, хотя доказательств этому методу профилактики in-stent trombosis вроде бы и нет.

Существуют ли в России лабораторные методы определения резистеннтности к клопидогрелю/аспирину?

Да, и у Вас в центре, и у нас, и во многих лабораториях в Москве это делается путем серийного определения агрегации с АДФ.
Более-менее принятым критерием полной резистентности к клопидогрелю считается подавление агрегации на <10%, неполной резистентности - на 10-29% и нормальной чувствительности - на >30% от исходного.

[Igor73]

Сообщение от audovichenko

Непереносимость мне за все время, что мы назначаем клопидогрель (с 1999 года - всем подряд), не встречалась ни разу. И аллергия не встречалась, хотя это даже как-то странно.

Пластик становится всё больше. И это хорошо У нас появились случаи аллергии на клопидогрель.

[audovichenko]

Сообщение от Igor73

Пластик становится всё больше. И это хорошо У нас появились случаи аллергии на клопидогрель.

Понимаешь, мы тут этот вопрос обсуждали с Олей birdname. Интересно то, что вроде не было - не было аллергии, а тут вдруг - да помногу . Собственно обсуждение-то было на тему "не может ли быть контрафакта"...

[Igor73]

Lau WC et al
Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.
Circulation. 2003 Jan 7;107(1):32-7.
Вывод: CYP3A4 активирует клопидогрель. Аторвастатин, другой субстрат CYP3A4, конкурентно ингибирует эту активацию. Использование статинов, не метаболизирующихся CYP3A4 и point-of-care определение активации тромбоцитов могут быть оправданы у пациентов, принмающих клопидогрель.
Нужно ли менять на 12 мес такой эффективный у этой категории пациентов аторвастатин на что-то другое после установки DES и начала терапии клопидогрелем? Или это что-то из разряда drug-drug interaction like иАПФ vs. аспирн?

[Igor73]

Сообщение от audovichenko

Да, и у Вас в центре, и у нас, и во многих лабораториях в Москве это делается путем серийного определения агрегации с АДФ. Более-менее принятым критерием полной резистентности к клопидогрелю считается подавление агрегации на <10%, неполной резистентности - на 10-29% и нормальной чувствительности - на >30% от исходного.

Анна Евгеньевна, у вас в клинике перед ТБКА этим пользуются? Или это пока сугубо научная идея?

[audovichenko]

Сообщение от Igor73

Нужно ли менять на 12 мес такой эффективный у этой категории пациентов аторвастатин на что-то другое после установки DES и начала терапии клопидогрелем? Или это что-то из разряда drug-drug interaction like иАПФ vs. аспирн?

Не нужно. Сейчас лень искать, но были проведены специальные исследования по КЛИНИЧЕСКОМУ взаимодействию аторвастатина и клопидогреля - оказалось, что ничего не меняется, т.е. по конечным точкам разницы нет.

Сообщение от Igor73

Анна Евгеньевна, у вас в клинике перед ТБКА этим пользуются? Или это пока сугубо научная идея?

В РНЦХ пользуются очень активно, у нас - на стадии исследования (т.е., мы метод используем только как контроль, а в НЦХ - как руководство к действию).
Спровоцированы наши исследования были тем, что у больных с острыми тромбозами (независимо от типа стентов) ретроспективно обнаруживались признаки резистентности.

[Arisha-B]

Сообщение от audovichenko

Спровоцированы наши исследования были тем, что у больных с острыми тромбозами (независимо от типа стентов) ретроспективно обнаруживались признаки резистентности.

Уважаемая Анна Евгеньевна, в случае выявления резистентности к плавиксу какова дальнейшая тактика ведения пациента?

[audovichenko]

Сообщение от Arisha-B

Уважаемая Анна Евгеньевна, в случае выявления резистентности к плавиксу какова дальнейшая тактика ведения пациента?

Увеличение дозы до появления признаков чувствительности по агрегограмме. Обычно хватает 300 мг однократно и 150 мг в течение недели с последующим переходом на стандартную поддерживающую дозу.
ЗЫ Это пока не ЕВМ