January 25th, 2011
New Study Finds Hydrochlorothiazide Inferior To All Other BP Drugs
Larry Husten, PHD
At the dosages most often used, hydrochlorothiazide (HCTZ), the most widely used antihypertensive agent in the world, is “consistently inferior” to all other drugs, according to a new meta-analysis published in JACC. Franz Messerli and colleagues performed a systematic review of studies that compared HCTZ to other drugs using 24-hour ambulatory blood pressure monitoring and found that the decrease in blood pressure with HCTZ (6.5 mm Hg systolic and 4.5 mm Hg diastolic) was significantly less than with ACE inhibitors (12.9/7.7 mm Hg), ARBs (13.3/7.8 mm Hg), beta-blockers (11.2/8.5 mm Hg), and calcium channel blockers (11.0/8.1 mm Hg).
The authors note that HCTZ is as effective as the other antihypertensive agents when blood pressure is measured in the office. They write that this suggests that HCTZ is likely less effective at night. Although HCTZ is widely perceived to be clinically effective in improving outcomes, Messerli and colleagues write that “all outcome studies were done with higher doses than the currently used 12.5 to 25 mg or with other thiazides such as chlorthalidone or indapamide.”
However, because HCTZ is “suboptimal” as monotherapy, that “should not prevent it from being useful in combination with” other agents, since many studies have found that HCTZ in combination with other agents yields an incremental reduction in blood pressure.
January 24th, 2011
Poor Justification for Compulsory Angiography Before Vascular Surgery
Harlan M. Krumholz, MD, SM
I recently heard a physician quote a paper from JACC to justify pursuing revascularization in an asymptomatic patient who was scheduled for major vascular surgery. This article is worth a close look in your journal club, even though it was published in 2009.
In their discussion, the authors summarize their findings as follows: “For patients in preparation for major vascular surgery, the present study shows that a strategy of ‘prophylactic’ coronary artery angiography for all patients at medium-high risk, followed by coronary revascularization as needed, is more effective in curbing the rate of post-operative cardiac events and death than is a conservative strategy of coronary angiography and revascularization performed on the basis of a positive noninvasive test.”
Your group should evaluate the quality of the study, particularly whether it is strong enough to affect practice.
The Design
The trial, from Italy, consecutively enrolled 208 patients (mean age, 74) who were scheduled for elective surgical treatment of major vascular disease and who had a revised cardiac risk index (RCRI) ≥2. The participants were randomized either to a selective strategy whereby noninvasive test results would guide the decision about angiography or to compulsory angiography. The researchers powered the study for a 10% reduction in the long-term and 30-day rates of major adverse cardiovascular events (MACE).
The Findings
As expected, the revascularization rate was higher in the compulsory-angiography group than in the selective-angiography group (58% vs. 40%). The two groups did not differ significantly in the MACE rate at 30 days, although it trended lower with the compulsory strategy (2.8% vs. 4.8%). At a mean follow-up of 58 months, the compulsory group had significantly better survival and freedom from cardiovascular events. The 4-year freedom from events was 87% in the compulsory group and 70% in the selective group (relative risk reduction, 59%; P=0.04).
My Analysis
First, I am amazed that every patient who met this study’s inclusion criteria was enrolled. (The article says that 672 patients were screened and that 464 had an RCRI <2. Note that 672 – 464 = 208, the number enrolled and randomized.) This trial may be the first ever in which all eligible patients opted to participate and gave informed consent. 100% participation — mighty impressive.
Second, is the result plausible? Revascularization was performed in 19 more patients in the compulsory group than in the discretionary group (61 vs. 42). The absolute difference in events at 4 years is 17%. For this intervention to be responsible for this difference, practically every person in the compulsory group who underwent revascularization would have had to derive a MACE benefit (angiography in its own right would not be expected to have an important effect on cardiac events and mortality). That is, the compulsory strategy produced 19 more revascularization procedures and prevented about 19 more cardiac events at 4 years. Is such an effect even possible, especially given the likelihood that some members of the selective group would eventually cross over and undergo catheterization and revascularization in a 4-year period? According to the published data, the number needed to treat for revascularization to achieve benefit in this trial was just about 1!
Finally, the JACC article does not list any registration of the study at clinicaltrials.gov, and a search at the site reveals no record of the trial, suggesting that it was never registered. Given that omission, it’s impossible to determine what the researchers declared about the study before it was performed.
A Better Source of Data
This amounts to merely an interesting pilot study whose results cannot trump those from the Coronary Artery Revascularization Prophylaxis (CARP) trial. In CARP, 510 patients in the U.S. were randomized to revascularization or no revascularization before major vascular surgery. No benefit of revascularization was demonstrated — either overall in the main trial or, as a CARP substudy showed, in the highest-risk subgroup. The bottom line is that the study from Italy should not be used as a justification for compulsory angiography or revascularization before vascular surgery.
What are your thoughts about this study? What would you say to a colleague who tried to justify an intervention based on its findings?
January 24th, 2011
AHA Estimates Cost of Heart Disease Will Triple by 2030
Larry Husten, PHD
The American Heart Association (AHA) is projecting that the cost to treat heart disease in the U.S. will triple by 2030, from $273 billion today to $818 billion. The AHA policy statement is published in Circulation. The AHA estimates that the incidence of stroke and heart failure will each grow by about 25% by 2030.
“These estimates don’t assume that we will continue to make new discoveries to reduce heart disease,” said Paul Heidenreich, chair of the AHA expert panel issuing the statement, in a press release. “If our ability to prevent and treat heart disease stays where we are right now, costs will triple in 20 years just through demographic changes in the population.”
January 21st, 2011
Heart Rhythm Society Advising DOJ in Investigation of ICD Implants
Larry Husten, PHD
The Heart Rhythm Society (HRS) has informed its members that it is “aware of an ongoing U.S. Department of Justice (DOJ) civil investigation of Implantable Cardioverter Defibrillator (ICD) implants” and that it has “agreed to assist in an advisory role to lend expertise concerning proper guidelines for clinical decision making.”
HRS explained that its role involved “reviewing information that does not include either identifiable patient or facility level data. Rather, we are providing insight on the field of electrophysiology to the DOJ.”
At this point it appears there will not be more information from HRS: “Because this is an ongoing investigation, HRS Staff or Leadership is not available for further comment. HRS will communicate additional information to its membership when permitted to do so by the DOJ.”
January 21st, 2011
To Arms! Or, Maybe Not?
Richard A. Lange, MD, MBA and L. David Hillis, MD
According to a recently published opinion piece in a British cardiology journal, enthusiasm for the transradial approach over the femoral approach in primary PCI is not justified.
The authors cite numerous problems with the radial approach compared with the femoral approach (i.e., up to a 10% crossover rate, prolonged procedure time, increased radiation exposure for the patient and physician) and a lack of compelling evidence that it reduces major adverse cardiac and cerebrovascular events in the setting of primary PCI. In conclusion, our colleagues from the other side of the pond — while acknowledging that radial access does offer clear benefit for purely diagnostic angiography and elective PCI — encourage us to keep a leg up (so to speak) when considering the radial approach for primary PCI.
Is the radial approach for primary PCI a passing fad…and likely to suffer the same fate as atherectomy and polyester leisure suits?
Do you perform primary PCI via the radial approach? If so, how often?
January 20th, 2011
Braunwald: Vorapaxar Problem Based on Intracranial Bleeding in Patients with History of Stroke
Larry Husten, PHD
A key detail has now emerged about the problems encountered with vorapaxar, Merck’s thrombin receptor antagonist that suffered a large setback last week. TIMI investigators in the TRA-2P TIMI 50 trial have been informed by Eugene Braunwald that the reason vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial was because of an increase in intracranial hemorrhage in these patients. Merck issued a press release yesterday summarizing the TIMI chairman’s announcement.
Here is Braunwald’s statement:
“The DSMB has communicated to us that based on all of the data (safety and efficacy) available to them from both trials, they recommend that subjects with a history of stroke not receive vorapaxar. They have observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit.”
“In contrast, on the basis of their risk/benefit assessment in patients without a history of stroke, the DSMB recommended to us that it is important that the trial continue to completion in the more than 20,000 subjects who qualified for the trial with myocardial infarction or peripheral arterial disease who have not had a stroke. On the basis of their recommendation, we and Merck remain committed to completing this important scientific investigation with a potential for a reduction in death and ischemic events in these patients.”
Bob Harrington, chair of a second large vorapaxar trial, TRACER, said that both the TRACER investigators and Merck “remain blinded to the data” so they don’t know the specific details behind the DSMB’s recommendation. Here is Harrington’s statement:
“We have chosen not to receive the details of the TRACER interim analysis (in other words, we [the investigators and sponsor] remain blinded to the data). All patients in TRACER are coming off the study drug and the trial is being closed out. Consequently, we have no reason to be unblinded at this point. We sent our investigators the actual DSMB letter about closing out TRACER but this makes no reference to specific data on either safety or efficacy. This is therefore different than the 2P situation where the majority of the patients remain on study medication and so the sites required futher clarification.”
In TRACER, 13,000 hospitalized ACS patients were randomized to placebo or vorapaxar in addition to standard care. Last week Merck announced that TRACER had accumulated the predefined number of primary and major secondary endpoints, but not all patients had received the drug for the prespecified one-year followup. In TRA-2P TIMI 50, more than 25,000 patients with MI, ischemic stroke, or peripheral vascular disease were randomized to either vorapaxar or placebo in addition to standard care for the secondary prevention of MI and stroke. Last week Merck said that vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial. The study drug will be continued in more than 20,000 patients with previous MI or peripheral disease.
January 19th, 2011
What PROSPECT Doesn’t Tell Us
Richard A. Lange, MD, MBA and L. David Hillis, MD
The PROSPECT trial provides some interesting insights about the mechanisms of thrombotic coronary artery disease, but how, if at all, should it change practice? Here are what the findings do and do not demonstrate:
What the PROSPECT study says:
In ACS patients treated with PCI, major adverse cardiovascular events that occurred during a median follow-up of 3.4 years were as likely to result from a nonculprit ( i.e., other than the originally stented) lesion as from the culprit lesion. These nonculprit lesions often were angiographically mild (≈30% stenosis) and were characterized (with IVUS) as having thin-cap fibroatheroma, a large plaque burden, a small luminal area, or some combination of these.
What the PROSPECT study doesn’t say:
- ACS most commonly results from mild lesions. Major cardiovascular events were equally attributable to recurrence at the site of PCI and to nonculprit lesions.
- Mild lesions with thin caps, large plaque burdens, and small lumens carry a high risk of causing MI and death. In fact, of the lesions with all three of these characteristics, only 18% resulted in a cardiovascular event, the most frequent of which was hospitalization for unstable or progressive angina (in 93% of patients). Death, MI, or cardiac arrest occurred in only 7% of patients.
- Patients should have IVUS of their entire coronary tree to identify “high risk” lesions. In this study, 1.6% of patients had complications (dissection or perforation) related to the 3-vessel imaging procedure. Furthermore, of the 222 lesions leading to events, only 55 were prospectively “identified” by IVUS; 118 occurred at the sites of lesions treated with PCI, and 49 occurred in distal vessels inaccessible to IVUS.
- Mild angiographic stenoses should undergo revascularization. No data exist to suggest that revascularization of “vulnerable” lesions prevents acute events. In fact, revascularization may be harmful: 13% of stented lesions were subsequently the site of a cardiovascular event.
Do you see any expanded role for IVUS after this study? Will you do anything different in your practice on the basis of these results?
January 19th, 2011
Review Raises Questions About Statins for Primary Prevention
Larry Husten, PHD
A Cochrane Review raises troubling questions about the evidence base supporting the use of statins for primary prevention. The Cochrane reviewers analyzed 14 randomized trials including 34,272 participants and found that statins were associated with significant reductions in overall mortality, fatal and nonfatal CV endpoints, and revascularization procedures. The reviewers found no evidence of harm.
However, the authors found “evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease.” They concluded that “only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.”
In an accompanying editorial, Carl Heneghan discusses the limitations of the trials under review, noting, among other limitations, that the power calculations in most of the trials were based on composite outcomes, that selective reporting of outcomes occurred in some trials, and that some trials reported no adverse outcomes at all. He concludes that “the most effective and cost-effective intervention for primary prevention in adults at low risk currently remains unclear” and argues that it is “unwise to use such studies to determine the overall benefits and harms to the population at risk and drive policy.”
January 18th, 2011
Study Supports a New Enhanced Form of CPR
Larry Husten, PHD
A study published in the Lancet lends support to a new form of CPR that uses a combination of two devices to provide three times more blood flow to the heart and brain than standard CPR. The first device is a small suction cup on the patient’s chest used to actively lift the chest and perform what is called active compression-decompression CPR. The second is an impedance-threshold device that uses a mask or tube to prevent passive air entry into the lungs.
The authors compared more than 1600 patients with cardiac arrest randomized to standard or enhanced CPR. Survival to hospital discharge with favorable neurological function occurred in 6% of patients receiving standard CPR and 9% of patients receiving enhanced CPR. Survival at one year was the same as the primary endpoint: 6% and 9%. The authors write that “for the first time” they “have shown that a new method of CPR increases hospital-discharge rates and 1-year survival, which are both associated with good neurological outcomes, by nearly 50%, compared with the current standard of care, closed-chest manual CPR.”
In an accompanying comment, Peter Nagele writes that it is too early to recommend widespread use of the device for out-of-hospital cardiac arrest, based on a lack of independent replication of the results and possible bias in the trial because of the the open use of the devices.
January 14th, 2011
FDA Warns About Severe Liver Injury Associated with Multaq (Dronedarone)
Larry Husten, PHD
The FDA has released a safety communication about severe liver injury associated with Multaq (dronedarone). The FDA said that information about the risk of liver injury would be added to the dronedarone label. The drug’s manufacturer, Sanofi-Aventis, has also sent a letter to healthcare professionals informing them of the warning.
The FDA is recommending that doctors advise their patients “to contact a healthcare professional immediately if they experience signs and symptoms of hepatic injury or toxicity while taking dronedarone.” In addition, doctors should “consider obtaining periodic hepatic serum enzymes,” but the FDA acknowledged that there is no evidence whether this step will prevent liver injury.
The safety warning is based on several reported cases of liver injury and failure, including two patients who required liver transplants 4.5 and 6 months after starting dronedarone treatment. In both cases no other causes for liver failure were found.
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