terça-feira, 27 de janeiro de 2009

BNP vs Symptom Heart Failure

BNP-Guided vs Symptom-Guided Heart Failure Therapy
The Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) Randomized Trial
JAMA Vol. 301 No. 4, January 28, 2009
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

JAMA. 2009;301(4):383-392.
Context It is uncertain whether intensified heart failure therapy guided by N-terminal brain natriuretic peptide (BNP) is superior to symptom-guided therapy.
Objective To compare 18-month outcomes of N-terminal BNP–guided vs symptom-guided heart failure therapy.
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.
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).
Main Outcome Measures Primary outcomes were 18-month survival free of all-cause hospitalizations and quality of life as assessed by structured validated questionnaires.
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)
Conclusion Heart failure therapy guided by N-terminal BNP did not improve overall clinical outcomes or quality of life compared with symptom-guided treatment.
Trial Registration isrctn.org Identifier: ISRCTN43596477

quarta-feira, 21 de janeiro de 2009


VADT published: Intensive glucose control fails to reduce cardiovascular eventsDecember 18, 2008 Michael O'Riordan
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 [1].
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.
"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."
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
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.
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.
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.
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.
"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."
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.
Dr Sherita Golden (Johns Hopkins) echoed Blumenthal's sentiments.
"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.
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.
Position statement on intensive glycemic control issued
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 [2].
"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.
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.
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."
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.
The scientific statement is also published in the Journal of the American College of Cardiology and Diabetes Care.Treat the cardiovascular risk factors
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.
"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."
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.
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.
"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."
Duckworth reports consulting fees from Novo Nordisk, GlaxoSmithKline, and Caremark and lecture fees from Sanofi-Aventis.
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: http://www.nejm.org.
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: http://circ.ahajournals.org.

sexta-feira, 2 de janeiro de 2009

FDA e prasugrel

FDA asks panel of heart doctors for help reviewing blood-thinning drug prasugrel.
The Wall Street Journal (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.
The AP (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."

terça-feira, 2 de dezembro de 2008

Impacto do ALLHAT

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

sexta-feira, 14 de novembro de 2008

raiva em pernambuco

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

quarta-feira, 24 de setembro de 2008

Profess: abstract

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

quinta-feira, 18 de setembro de 2008

editorial Norman Kaplan: HYVET e ONTARGET

Editorial Recent Clinical Trials
The Good, the Bad, and the Misleading Norman M. Kaplan
Results of 3 major clinical trials on the treatment of hypertension have been published recently1,2 or presented.3 In addition, the validity of data provided in an often-quoted publication of another trial4 that had a major impact on nephrological practice5 has been seriously questioned.6
First, the good trial, Treatment of Hypertension in Patients 80 Years of Age or Older,1 addressed a major unsettled issue: should antihypertensive drug therapy be given to the very elderly? The need for such a study is obvious, because people >80 years of age are the fastest growing part of our population, and systolic hypertension is almost invariable among them.7 The few data available previously on the benefit versus danger of treating them were not encouraging.8
Fortunately, Treatment of Hypertension in Patients 80 Years of Age or Older turned out very well, so well that it was stopped prematurely after an average of 1.8 years of treatment because of the strong evidence of benefit with an average blood pressure that was 15/6 mm Hg lower than in the placebo group. Death from cardiovascular disease was reduced by 23%, death from any cause by 21%, stroke by 30%, and heart failure by 64%. As with all trials, some methodologic issues are noted: (1) the subjects were healthier than most people over age 80 years; (2) only one third had isolated systolic hypertension, the usual form of hypertension in the elderly; (3) only half reached the goal of 150/80 mm Hg; and (4) therapy was limited to the diuretic indapamide and the angiotensin-converting enzyme (ACE) inhibitor perindopril.
Nonetheless, the outcome data are very impressive and will call for extension of drug treatment to patients at any age who are not suffering from terminal illness or severe dementia. The suggestive evidence that ACE inhibition may reduce the risk of Alzheimer disease by increasing degradation of amyloid-β9 will likely add to the rush toward ACE inhibitor therapy in the elderly.
The Misleading Trial
The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) compared an ACE inhibitor with an angiotensin receptor blocker (ARB) and with a combination of the ACE inhibitor and the ARB.2 The trial was patterned after the Heart Outcomes Prevention Evaluation Trial10 with the same principal investigators. It was designed to show noninferiority of the ARB to the ACE inhibitor, which was shown. In particular, the equal cardioprotection by the 2 agents should settle the claim than ARBs are less effective than ACE inhibitors for myocardial protection. The combination was associated with more progressive renal dysfunction, likely from excessive lowering of blood pressure in vulnerable patients.
In view of the equivalence of the 2 drugs, a not-surprising result, the major issue leading clinicians to choose one or the other would logically depend on adverse effects. In ONTARGET, the incidence of the most common adverse effect of ACE inhibitors, cough, was reported in only 4.2% to be the cause for discontinuation of the ACE inhibitor, whereas the same dose of the same ACE inhibitor was the cause for discontinuation in 7.3% of the Heart Outcomes Prevention Evaluation Trial (both 4.2% and 7.3% are below the usual reported incidence of cough, 10% to 15%, but the larger incidences are for the occurrence of cough and not the cause of discontinuation of treatment).
Why the lower incidence of ACE inhibitor–induced cough? The reasons are obvious and should have at least been mentioned in the discussion of ONTARGET if not taken into account in establishing the protocol. These are as follows: (1) 60% of enrollees were already on an ACE inhibitor, weeding out those who were intolerant; (2) those who were known to be intolerant to an ACE inhibitor were shunted to a parallel study, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease, which has not yet been published; and (3) ramipril was given for a 3- to 4-week run-in so that, again, those who were quickly intolerant of an ACE inhibitor were not enrolled.
Thus, the major adverse effect of ACE inhibitors was minimized by design, negating the well-known lesser adverse effect profile of ARBs. This may be the reason why the editorialist commenting on ONTARGET stated, "ARBs have more side effects than ACE inhibitors,"11 despite the common knowledge that they do not.12
The Unpublished Trial
Results of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension Trial were presented as a "late breaker" at the March 2008 meeting of the American College of Cardiology, but as of June 30, 2008, the data remained unpublished. A preliminary publication describes excellent control of blood pressure in both arms, the combined diuretic plus ACE inhibitor and the combined calcium channel blocker plus ACE inhibitor.13 The oral report indicated that the combination of ACE inhibitor and calcium channel blocker was much better than the diuretic and ACE inhibitor in reducing all of the end points.
Obviously, the publication of the results of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension Trial will be of great interest. If, as reported, it shows better effects of combining a calcium channel blocker over a diuretic, and if this finding is replicated in another large randomized, controlled trial, current practice may need to be modified.
The Bad Trial
During their review of the literature to prepare a meta-analysis of the effect of monotherapy and combination therapy of inhibitors of the renin-angiotensin system on proteinuria in patients with renal disease, Kunz et al14 stated that they, "excluded one eligible trial4 because of serious implausibilities that contact with the publishing journal could not resolve." These included a highly unusual balance in the distribution of 3 key baseline variables across 3 treatment groups, discrepancy between the reported statistical method and the results in the article, and problems with patient satisfaction. In a separate letter to the editor of The Lancet, where the original article4 was published, Kunz et al6 went even further in their critique stating, "The number and seriousness of the inconsistencies found in the Nakao article led us to wonder whether it is possible that this is only a case of extremely sloppy reporting or a hint toward more severe problems with the data." This could be of little concern except that the results have been accepted by expert nephrologists5,15 and have been incorporated into clinical practice. Perhaps the main conclusion from this unfortunate episode is that reviewers and journal editors should be much more careful before publishing novel results and much quicker to admit mistakes.
Large clinical trials are hard to do and expensive, so that, other than for some landmark trials sponsored by the National Institutes of Health, only pharmaceutical companies are willing to pay for them. The marketers of telmisartan, used in ONTARGET, are to be congratulated for their willingness to fund trials where their products might not be better than the comparator. However, the former editor of the British Medical Journal, Richard Smith, believes that substantial biases are virtually inherent in clinical trials and that journals should only publish critiques of trials, so they could, "prevent journals from being an extension of the marketing arm of pharmaceutical companies in publishing trials that favor their products."16
Dr Smith is not the first to call attention to the dangers of designing and reporting clinical trials. Nonetheless, clinical trials are needed to inform clinical practice, as more and more drugs are marketed. Moreover, other than occasionally from the National Institutes of Health, pharmaceutical companies are virtually the only current source of funding of large-outcome trials. Their results should be published in peer-reviewed journals, but caution must be taken in accepting their results to be more than marketing tools. Their study design should be independently reviewed before initiation, and rigorous examination of their results should be provided by peer reviewers with statistical expertise.

Acknowledgments Disclosures

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


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