ATLANTA (EGMN) – The first prospective, randomized trial to compare two different diuretic doses in patients with acute decompensated heart failure showed no clear-cut advantage to either a low or high dose, but the results may have shown a hint that higher doses have a few advantages, study investigators said.

Among experts not involved with the trial, opinion split on whether any valid difference by dose could be inferred from a study that failed to show statistically significant differences in its primary end points.

“The top-line, take-home results were no differences,” between a low or high furosemide dose, or between twice-daily bolus injections or continuous infusion, Dr. G. Michael Felker said at the annual meeting of the American College of Cardiology.

“But when you look at the totality of the data, there are a lot of suggestions that you get quicker, more favorable results with the high dose,” including greater decongestion, a bigger reduction in blood levels of natriuretic peptide, and greater symptom relief,” said Dr. Felker, a cardiologist and heart failure specialist at Duke University in Durham, North Carolina.

“If you’re a practicing physician, there were important trends that suggest the higher-dose strategy had some favorable effects,” said Dr. Christopher M. O’Connor, co–principal investigator on the study and director of the Duke Heart Center. “We have no standard treatment for acute heart failure with diuretics. These results suggest a way to standardize care. Sometimes you need to make decisions based on imperfect data, on trends and secondary end points. These are the best available data in the world today on how to choose a furosemide dose.”

Others were less sure that results from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE) trial favored the higher furosemide dosage for patients hospitalized with acute decompensated heart failure.

“Based on this trial, I don’t think there is a difference” between the low and high doses used, commented Dr. Scott D. Solomon, a cardiologist at Brigham and Women’s Hospital in Boston. “You still have to look at the overall trial results,” and in this case they showed no significant difference between the doses tested, he added.

“Many of us have been concerned that high-dose furosemide may hurt patients, and lead to cardiorenal hypoperfusion that may account for a lot of the negative outcomes that happen when we discharge patients,” but this study didn’t show this, said Dr. Douglas Mann, professor and chief of the cardiovascular division at Washington University in St. Louis. Overall in the trial, patients “did a little better with symptoms” with the higher dose, “and you pay a small price with a slightly higher rise in serum creatinine levels.” The new findings “will have a major impact by giving us a baseline on how to approach treatment. One can take a conservative strategy at first, and then maybe escalate to a higher dose, which will probably be safe. The results tell you that you can decongest patients a bit more without excessive renal risk.”

DOSE enrolled 308 patients at U.S. hospitals within 24 hours of admission for acute decompensated heart failure. The amount of intravenous furosemide they received depended on the oral dose on which they had been maintained prior to hospitalization. Patients randomized to the low-dose group received the identical daily dose of furosemide they had been on before entering the hospital, from 80 to 240 mg/day. Patients randomized to the high-dose group received a daily dose of 200-600 mg/day, 2.5-fold higher than their usual oral dose. Patients who had routinely received a different loop diuretic before hospitalization had their prehospitalization dose converted to its furosemide equivalent. Patients also underwent a second, independent randomization based on whether they received the drug in hospital as a twice-daily bolus injection or as continuous infusion. In-hospital treatment continued for an average of about 60 hours.

Enrolled patients had an average age of 66, nearly three-quarters were men, and nearly three-quarters had been hospitalized for heart failure within the prior year. Their average left ventricular ejection fraction was 35%, their average serum creatinine level was 1.6 mg/dL, and their average serum level of N-terminal–pro brain natriuretic peptide (NT-proBNP) was more than 7,000 pg/mL. The study protocol allowed the diuretic dose to increase if needed after the first 48 hours on treatment, and about 25% of patients underwent this boost, especially patients randomized to the low-dose arm.

The study’s main efficacy end point was each patient’s cumulative self-assessment of symptoms at five points during the first 3 days of treatment (at 6, 12, 24, 48, and 72 hours after diuretic treatment began). The bolus and continuous infusion routes showed no difference for this outcome. The low- and high-dose groups also showed no statistically significant difference, but the high-dose regimen produced an improvement in symptoms that just missed statistical significance, at P = .06.

The primary safety outcome was the average change in serum creatinine 72 hours after onset of treatment, and both pairs of treatment produced small, virtually identical creatinine changes.

During 60 days of follow-up, neither randomization led to significant differences in a combined outcome of death, rehospitalization, or emergency department visits.

In three secondary efficacy measures at 72 hours, the high dose produced significantly better results compared with the low dose: dyspnea severity, total weight loss, and total net fluid volume loss. The high dose also produced a larger reduction in serum levels of NT-proBNP that just missed statistical significance, at P = .06.

The high-dose regimen also linked with worsening renal function at 72 hours, but the effect was transient with the difference disappearing by a week after treatment onset. At 72 hours, 23% of patients in the high-dose group and 14% in the low-dose group had a 0.3-mg/dL or greater rise in their serum creatinine level, a statistically significant difference.

Regardless of Best Furosemide Dose, Ultrafiltration Remains Optimal Treatment

The DOSE findings will reassure physicians that even smaller diuretic doses, given as boluses, have some efficacy, according to Dr. Maria Rosa Costanzo, medical director of the heart failure and pulmonary arterial hypertension programs at Midwest Heart Specialists in Naperville, Illinois.

If a physician is going to use a diuretic for heart failure, it should be at the lowest effective dose, she said.

However, both low-dose and high-dose furosemide regimens in patients hospitalized with acute decompensated heart failure are associated with relatively high rates of hospital readmissions because diuretics do not effectively reduce total sodium burden, which is an important cause of congestion in these patients, Dr. Costanzo said. Other drug treatments, including vasopressin antagonists and adenosine receptor blockers, have the same limitation.

“The only treatment that effectively reduces sodium burden is ultrafiltration, also known as aquapheresis. It is therefore the best treatment for heart failure patients with recurrent, acute congestion episodes,” she said.

“My associates and I showed the superiority of ultrafiltration over intravenous treatment with a loop diuretic in results from the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial [J. Am. Coll. Cardiol. 2007;49:675-83]. This multicenter study randomized 200 patients, and showed that ultrafiltration resulted in significantly better weight and net fluid loss within 2 days of treatment. During 90-day follow-up, the ultrafiltration patients had significantly fewer rehospitalizations and significantly fewer days spent rehospitalized compared with diuretic-treated patients,” Dr. Costanzo said.

Unfortunately, ultrafiltration has not caught on as the preferred method for managing acute heart failure in U.S. patients, she added. “It may be because only a single study has been done, and some physicians may want results from a confirmatory study before they adopt ultrafiltration. Funding constraints have kept us from conducting another study.”

In addition to lack of a confirmatory study, other factors helped keep diuretics on top: First is habit; diuretics have traditionally been the primary therapy for acute decompensation, Dr. Costanzo pointed out. “Also, the small company that produces the ultrafiltration equipment, CHF Solutions, has had a limited marketing effort, although this may change now that a larger company, Gambro, acquired CHF earlier this year. Another important issue is availability. Although most centers with a heart failure program have access to ultrafiltration, many U.S. patients with acute heart failure decompensation receive treatment at hospitals without a heart failure center.”

Despite these limitations, “I firmly believe that ultrafiltration is the preferred treatment. Diuretics are less effective because they remove hypotonic fluid, without relieving sodium burden. Diuretics also enhance neurohormonal activation, another detrimental effect on patients. Ultrafiltration is unique in its ability to remove isotonic fluid, which gets sodium out of patients. No treatment of acute decompensation can be effective unless it reduces a patient’s sodium burden,” Dr. Costanzo said.

“A study now in progress, run by the [U.S.] National Heart, Lung, and Blood Institute’s Heart Failure Network, the Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome (CARRESS) trial, involves a second comparison of ultrafiltration and diuretic treatment, specifically in patients who have worsening renal function during their decompensation episode.”

The DOSE study was funded by the U.S. National Heart, Lung, and Blood Institute. Dr. Solomon and Dr. Mann had no disclosures relevant to this study. Dr. Felker has financial relationships with Corthera, Geron, Roche Diagnostics, Cytokinetics, BGMedicine, and Amgen. Dr. O’Connor has received grants from Roche Diagnostics and GE Healthcare. Dr. Costanzo has served as speaker and consultant to, and received research support from, CHF Solutions.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

亚特兰大(EGMN)——首项在急性失代偿性心衰患者中比较2种不同剂量利尿剂的前瞻性随机试验表明，无论大剂量或小剂量都没有明显的优势，但该试验的研究者称，试验结果提示，大剂量的利尿剂可能具有一些优势。

 

是否可以基于一项主要终点无显著统计学差异的试验推断出不同剂量之间存在有效差异，对于这一问题，没有参与该试验的专家们各持己见。

 

在美国心脏病学会2010年年会上，G. Michael Felker博士说，无论是大剂量与小剂量呋塞米相比，还是一日2次团注与连续输注相比，“有关主要终点的最重要结果均无差异”。

 

作为一名心衰治疗专家，美国北卡罗来纳州达勒姆市杜克大学的心脏科医生Felker博士说：“但纵观所有试验数据，你会很快发现这些数据实际上提示了很多信息，大剂量组的结果更好，包括充血减轻的效果更明显，血中利钠肽水平的下降幅度更大，并且症状缓解也更明显。”

 

作为该试验的主要研究者之一，Duke心脏中心的Christopher M. O’Connor博士说：“如果你是一名执业医师，你会发现试验结果存在一些重要的趋势，都提示大剂量的用药策略更具优势。目前，对于急性心衰，尚未制定利尿剂治疗的标准。这些试验结果提示了一种将治疗标准化的方法。有时，我们只能基于并不完美的数据或趋势或次要终点来作出临床决策。对于如何选择呋塞米的用药剂量这一问题，目前是全球可获取的最高质量的数据。”

 

对于这项名为“急性心衰患者利尿剂优化策略评价” (DOSE)的试验支持大剂量呋塞米治疗因急性失代偿性心衰而入院的患者更具优势这一结果，其他人则表示并不那么肯定。

 

美国波士顿布莱根妇女医院的心脏科医生Scott D. Solomon博士评论道：“基于该试验，我并不认为试验所采用的大剂量与小剂量之间存在差异。” Solomon博士补充道：“我们还是应该看总的试验结果”，这样的话，两种试验剂量之间并无显著差异。

 

美国圣路易斯华盛顿大学教授兼心血管系主任Douglas Mann博士说：“很多医生都一直担忧大剂量的呋塞米可能会给患者带来伤害，导致心肾灌注不足从而引发一系列的不良后果，并且这些后果可能在患者出院时才出现”，不过该试验并未证实这一点。总的来看，该试验中大剂量组的患者“在症状改善方面有些优势，而血清肌酐水平的升幅仅略高于小剂量组，代价不算大。”这些新的试验发现“为我们如何制定治疗策略提供了基础参考，因此影响颇大。我们可以先采取保守的治疗策略，然后再逐渐加大剂量，大剂量用药很可能是安全的。试验结果告诉我们，可以通过加大剂量来进一步减轻充血，而不会导致肾脏风险增加。”

 

DOSE试验共纳入了来自美国医院的308例患者，所有患者均在因急性失代偿性心衰入院后24h内入选试验。患者所接受的静脉用呋塞米的剂量取决于入院前其使用的口服维持剂量。经随机分组后，小剂量组患者接受的呋塞米日剂量与其入院前相同，即80~240 mg/d。大剂量组患者则每日接受200~600 mg/d的呋塞米，这是其常用口服剂量的2.5倍。对于入院前常规服用另一种袢利尿剂的患者，则将其入院前的用药剂量换算成等效的呋塞米剂量。还基于患者在院内是接受一日2次团注或连续输注，进行了第2次独立的随机分组。院内治疗平均持续60h左右。

 

受试者的平均年龄为66岁，男性几乎占到了3/4，并且将近3/4的受试者在前一年内都曾因心衰而住院治疗。受试者的平均左室射血分数为35%，血清肌酐的平均水平为1.6 mg/dl，血氨基末端脑利钠肽前体(NT-proBNP)的平均血清水平大于7,000 pg/ml。试验方案允许在治疗48h后，按需加大利尿剂的剂量。大约25%的患者接受了这一剂量增加程序，尤其是那些被随机分配至小剂量组的患者。

 

该试验的主要疗效终点为治疗前3天(利尿剂治疗开始后6、12、24、48和72h)每位患者基于5点量表对其症状的自我评价累积结果。从该结局指标来看，团注与连续输注这2种给药方式之间无显著差异。大剂量组与小剂量组相比，也没有显著的统计学差异，但大剂量组的症状改善更为明显，几乎达到统计学显著性水平，P = 0.06。

 

主要的安全性结局指标是治疗开始后72h血清肌酐的平均变化。结果显示，无论采用哪种给药途径，无论采用哪种剂量，肌酐的变化都较小且各组基本相同。

 

在为期60天的随访期内，无论基于哪一次随机分组，死亡、再次入院或急诊科就诊这一复合结局指标均无显著的组间差异。

 

于治疗后72h测量的3项次要疗效指标显示，大剂量组的疗效显著优于小剂量组：呼吸困难的严重程度、体重减轻的总量以及总的液体净失量。而且，大剂量组NT-proBNP血清水平的下降幅度也更大，几乎达到统计学显著性水平，P = 0.06。

 

大剂量组患者治疗后72h的肾功能更差，但该效应是一过性的，治疗后1周这种差异就消失了。治疗后72h，大剂量组23%的患者和小剂量组14%的患者血清肌酐水平升高≥0.3 mg/dl，差异有统计学意义。

 

无论呋塞米的最佳剂量如何，超滤治疗仍是最佳的治疗选择

 

美国伊利诺州内珀维尔市中西部心脏专科医院心衰与肺动脉高压治疗组医学主管Maria Rosa Costanzo 博士称，DOSE试验的发现又一次令医生确信即便团注小剂量的利尿剂，也会产生一定的疗效。

 

Costanzo 博士说，如果医生准备采用利尿剂来治疗心衰，那么应从最小有效剂量开始。

 

不过，Costanzo 博士指出，对于因急性失代偿性心衰而入院的患者，无论采用的是小剂量还是大剂量的呋塞米治疗方案，再次入院的发生率都相对较高，这是因为利尿剂不能有效减轻总的钠负荷，这正是导致这类患者心脏充血的重要原因之一。包括血管加压素拮抗剂和腺苷受体阻滞剂在内的其他药物治疗也存在类似的局限性。

 

Costanzo 博士说：“可有效减轻钠负荷的唯一治疗方法是超滤治疗，也称为水液置换治疗(aquapheresis)。因此，这也是复发性急性充血发作的心衰患者的最佳治疗。”

 

Costanzo 博士说：“我和同事开展了一项名为‘比较超滤治疗与静脉用利尿剂治疗因急性失代偿性心衰而入院的患者’(UNLOAD)的试验，结果表明，超滤治疗优于经静脉袢利尿剂治疗(J. Am. Coll. Cardiol. 2007;49:675-83)。这项多中心试验将200例患者随机分组，结果显示，从治疗2天内体重和液体净失量来看，超滤治疗具有显著的优势。在为期90天的随访期内，接受超滤治疗的患者再次入院的发生率显著低于接受利尿剂治疗的患者，即便再次入院，住院时间也显著缩短。”

 

Costanzo 博士补充道，遗憾的是，在美国，超滤治疗尚未成为急性心衰患者的首选治疗方法。“这可能是因为到目前为止只开展了一项相关试验，部分医生可能想等到确证性试验的结果出现之后再开始采用超滤治疗。由于经费有限，我们无法再实施另一项试验。”

 

Costanzo 博士指出，除了缺少相应的确证性试验之外，有助于利尿剂始终处于首选地位的其他因素包括：首先，习惯成自然；利尿剂历来都是急性失代偿患者的主要治疗药物。“其次，生产超滤治疗设备的是一家名为CHF Solutions的小公司，该公司在市场营销方面的实力有限，不过如今这种情况可能会有所改善，今年早些时候一家规模更大的公司Gambro成功收购了CHF。此外，另一个重要因素是治疗的可及性。虽然大多数成立了心衰治疗组的医疗中心都有超滤治疗设备，但在美国，许多急性心衰失代偿患者都是在没有心衰治疗中心的医院接受的治疗。”

 

Costanzo 博士说，尽管存在以上局限性，但是“我坚信，超滤治疗应该成为首选的治疗方法。利尿剂的疗效不及超滤治疗，因为利尿剂只能清除低渗液体，而无法减轻钠负荷。而且，利尿剂还会促进神经内分泌激活，这对于心衰患者又是另一大有害效应。超滤治疗清除等渗液体的能力是独一无二的，其能将钠排出体外。对于急性失代偿患者而言，只有能够减轻钠负荷的治疗才是真正有效的。”

 

“目前，美国国家心肺和血液研究所心衰网络正在开展一项名为‘超滤治疗对急性失代偿性心衰患者和心肾综合征患者的疗效’(CARRESS)的试验，该试验将再一次比较超滤治疗与利尿剂治疗的疗效，尤其对于那些在失代偿期内肾功能不断恶化的患者。”

 

DOSE试验由美国国家心肺和血液研究所资助。Solomon博士和Mann博士声明无相关利益冲突。Felker博士声明与Corthera、Geron、罗氏诊断、Cytokinetics、BGMedicine和安进公司之间存在经济利益关系。O’Connor博士声明接受了罗氏诊断公司和通用电气医疗集团提供的研究经费。Costanzo博士任CHF Solutions公司的讲演者兼顾问，并接受了该公司提供的研究经费。