March 4th, 2011
Legislating CVD Screening Tests in Texas
Amit Khera, MD, MSc
Imaging tests for cardiovascular risk assessment hold great promise. Both coronary artery calcium (CAC) scanning and carotid intima-media thickness (CIMT) testing have been shown in multiple prospective studies to predict cardiovascular outcomes and, more recently, to improve risk reclassification based upon the Framingham Risk Score. Coupled with frustrations about the performance of the Framingham Risk Score as well as the movement towards personalized medicine, it is understandable why there is great enthusiasm for broader implementation of these tests. This enthusiasm has taken tangible form in the Texas Atherosclerosis Imaging Bill, HB 1290, which was passed by the Texas Legislature in 2009 mandating insurance coverage for CAC scanning or CIMT testing every 5 years in an accredited laboratory for men aged between 45 and 75 years and women aged between 55 and 75 years who also have diabetes or “a risk of developing coronary heart disease, based on a score derived using the Framingham Heart Study coronary prediction algorithm, that is intermediate or higher.”
The question is: in our intention to do something, are we sure we know what it is we are doing? And more importantly, is our understanding of these tests and their full implications for population level implementation at a stage where legislative action is warranted? In a recent editorial, I tried to address these issues by taking a closer look at Texas HB 1290.
While some have argued that legislative coverage mandates are never warranted, there are some prerequisite questions that should reasonably be asked before considering such tools: How many people will this affect? What are the costs? What are the risks? How many lives can we save or CVD events can we prevent? Is there agreement on how to use these tests and interpret the results? What do the experts say about how we should use these tests? What do patients think? Insurers? Public health officials?
To the extent that these data are available in public testimony and records, it seems that most of these questions were either not addressed or not in sufficient detail commensurate with such a novel bill with broad implications. In my calculations, if all people in the designated age range and risk category specified by the bill were scanned, this group would comprise 2.4 million individuals with an initial cost of $480 million. Those are astounding figures that alone should give us pause to ask “what are we getting in return?” To be sure, there would almost certainly be a large number of patients at high risk for CVD events who would be detected (~285,000 by my calculations), and intensifying preventive therapies in this group may globally improve cardiovascular outcomes.
However, this later point has several caveats. First of all, the majority of patients in age and risk category would already have an indication for statin therapy, and it is unclear what additional benefit is gained from intensification of statins in primary prevention. In addition, as we move closer to “treat all” (as we are likely to see additional groups recommended for lipid lowering therapy in the upcoming ATP IV), the utility of these tests from a population level are diminished. Finally, the reduction in CV events would have to be balanced against the radiation risks and incidental findings in this asymptomatic population. It is possible (or even probable) that these atherosclerosis imaging tests would still end up favorable, but these calculations were certainly warranted before seeking a legislative mandate.
Many detractors of atherosclerosis imaging tests have focused on the lack of randomized clinical trials evaluating the impact of these tests on improving clinical outcomes. While a critical point, there are several other more proximal issues that need to be clarified before pondering a legislative mandate. For example, the “intermediate risk” group is a very logical target based upon a Bayesian approach, but this group can be defined in many different ways. Just shifting this group from 10-20% 10-year risk to 6-20% 10-year risk would add several hundred thousand additional Texans for screening eligibility. In addition, focusing on the 10-20% risk group would shortchange the potential utility of these scans in women as there are few “intermediate risk” women in the population, and more than four times as many men compared with women are eligible for atherosclerosis imaging under HB 1290. In addition, there is still no universal consensus on the appropriate interpretation of and response to specific test results. In my personal practice, I have assumed the care of patients that were previously treated as if they have a “disease” when they have small amounts of coronary calcium at a younger age, and others who were told they were just fine with the same findings.
I have two disclosures for this blog: 1) I am a Texan 2) I order coronary artery calcium scans. For the former, I felt the need to look closely at this legislation to evaluate its global ramifications for people in this state. For the latter, I have detailed discussions with each patient about the risks and benefits and how we may change our management based upon the results before we order these tests. But the leaps of evidence and understanding required for individual patient-doctor decisions, to population screening, to legislative mandates are vast and we must tread carefully before we invoke legislative action.
March 4th, 2011
13th Annual Echocardiography Conference: State-of-the-Art 2011
CardioExchange Editors, Staff
March 3rd, 2011
Pennsylvania Hospital: 141 Patients Received Unnecessary Stents
Larry Husten, PHD
A hospital in western Pennsylvania says that at least 141 heart patients received coronary stents that weren’t needed, according to an article by Luis Fabregas in the Pittsburgh Tribune-Review. Westmoreland Hospital in Greensburg, PA has informed the patients, and the two interventional cardiologists who performed the procedures have resigned. The hospital says that it will cooperate with the Office of the Inspector General.
The episode had its origins early in 2010 when “several unidentified physicians alerted hospital officials about a pattern of excessive stent use in the cardiac catheterization laboratory,” according to the news report. The hospital then initiated an external review of the seven cardiologists and two interventional radiologists who implanted stents at the hospital. The first preliminary review was completed in December and raised concerns about excessive stent implantation by two cardiologists, Ehab Morcos and George Bousamra. They resigned their privileges at the hospital on January 12th when they were asked about the results of the review.
The hospital then began a thorough review of all 753 cases performed in 2010 by the 2 cardiologists. The review by 8 independent cardiologists found that 149 stents had been implanted unnecessarily in 141 people. The hospital has now hired an “internationally recognized university” to provide quality control for the cath lab.
“The fact that we investigated this quickly, in an in-depth and professional manner, in a transparent way, should signal that we’re committed to having a transparent organization,” said the hospital’s CEO.
The incident is reminiscent of a similar case in Maryland, where the formerly prominent interventional cardiologist Mark Midei has been accused of implanting hundreds of unnecessary stents. Many observers have wondered whether the Midei incident would spark similar investigations in other communities. It appears that the concerns about the Pennsylvania case were first raised when the Midei case began to receive public attention.
March 3rd, 2011
5-Year Followup of ACCORD: Still No Support For Intensive Glucose Lowering
Larry Husten, PHD
Long-term followup of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial has once again failed to support routine intensive glucose lowering in high-risk type 2 diabetics. In 2008, as reported in the New England Journal of Medicine, the intensive glucose-lowering regimen (target glycated hemoglobin level of <6%) was terminated early after an increase in mortality was observed in that group, and all patients received standard glucose-control therapy (target glycated hemogloblin level of 7.0% to 7.9%).
Now, a new paper in NEJM reports the 5-year results of the trial, after 3.7 years of intensive glucose-lowering treatment and up to 17 months of additional followup. Mortality at 5 years was 19% higher in the intensive-control group (7.6% in the intensive-therapy group versus 6.4% in the standard-therapy group). By contrast, the incidence of nonfatal myocardial infarction was lower in the intensive-therapy group, although cardiovascular deaths were higher in this group.
In their conclusion, the ACCORD investigators write that the results “suggest a lower limit for glycemic targets, achieved with the use of multiple combinations of currently available approaches.”
March 2nd, 2011
A DOSE of Reality: The Challenges of Comparing Effectiveness
Harlan M. Krumholz, MD, SM
An ideal paper for your next journal club — “Diuretic Strategies in Patients with Acute Decompensated Heart Failure” — was just published in NEJM, by the NHLBI Heart Failure Clinical Research Network. In this study (called DOSE), patients hospitalized with heart failure were randomized to receive different diuretic regimens based on dose and mode of administration. The authors concluded that “there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose.” The editorialist stated, “Since a high-dose regimen may relieve dyspnea more quickly without adverse effects on renal function, that regimen is preferable to a low-dose regimen.”
There are at least five issues here that might be worthy of your attention.
1. The topic. Diuretics were introduced in the 20th century to treat heart failure, replacing the rigid Southey’s tubes that were inserted subcutaneously to drain fluid. Thiazide diuretics were introduced in 1958, and furosemide, the first loop diuretic, was approved in 1966. This agent is now standard therapy for patients with heart failure. What is remarkable — and worth some reflection — is that despite using loop diuretics for 45 years now, we still do not have essential evidence to support decisions about dosing and mode of administration. This study responds to the clamor for comparative effectiveness trials — and should give us pause about what else we are doing in clinical practice with little evidence to guide us.
2. The primary outcomes. The primary efficacy endpoint (there was also a safety endpoint) was the patient’s global assessment of symptoms, which was quantified as the area under the curve (AUC) of serial assessments from baseline to 72 hours. The authors describe the assessment as follows:
Patients were asked to self assess both their general well being (PGA) and their level of dyspnea using a visual analog scale (VAS) method. For PGA, patients marked their global well being on a 10 cm vertical line, with the top labeled “best you have ever felt” and the bottom labeled “worst you have ever felt.” For dyspnea, the labels were “I am not breathless at all” and “I am as breathless I have ever been.” The VAS was scored from 0 to 100 by measuring the distance in millimeters from the bottom of the line. The patient was unaware of the numerical value of their response.
Kudos to the research team for caring about patient-reported outcomes and attempting to translate those outcomes into a useful metric. However, interpreting the results is a challenge. For the comparison of bolus versus continuous infusion, the mean AUCs were 4236 and 4373, respectively (P=0.47). For the comparison of high- versus low-dose therapy, the values were 4430 and 4171, respectively (P=0.06). The authors considered a 600-point difference in AUC to be clinically important based on prior studies and thus concluded that there were no significant between-group differences in the primary efficacy endpoint, either statistically or clinically. Although these conclusions seem appropriate, it’s difficult to know what a 600-point difference really means in terms of the patient’s experience. A few examples from the authors would have been helpful.
3. The power calculation. With only 308 patients, this study was small by the standards of most RCTs measuring patient outcomes in heart failure. The sample size calculation was based on 88% power to detect a 600-point difference in the AUC of global assessment scores — and on 88% power to detect a difference of 0.2 mg/dL in the change in creatinine level between groups (the primary safety endpoint). I have no quibble with these calculations (though I do wonder why they picked 88%), but the small number of patients makes it difficult to do much with exploratory analyses by subgroup or different outcomes. The investigators adjusted the significance level for the primary outcomes, stating that the threshold would be a P value of <0.025. In doing this, they treated each trial within the 2×2 factorial design as a separate study with two endpoints.
One statistic that would have been useful to see in this paper is the confidence intervals for the difference in the primary endpoints, so that we could see what kind of differences cannot be excluded based on the results. Remember, the study was not designed to show that the groups were similar; it was designed to test if they were different. The conclusion, appropriately enough, was that there were no significant differences, but your questions now might be: “Are the treatment groups similar? What kind of differences can be excluded?”
4. The secondary analysis and adjustment for multiple comparisons. The investigators conducted many secondary analyses and, for these, set a P value of 0.05 as the threshold for statistical significance. Most of these endpoints did not differ between the groups, but there were some findings that bear discussion:
- In the high- versus low-dose comparison, the difference in the area under the curve at 72 hours for dyspnea met the criteria for statistical significance (4668 vs. 4478, respectively; P=0.04) — a point highlighted by the authors in the discussion. However, with so many comparisons conducted, a P value of 0.04 should hardly be considered significant. Furthermore, the difference between groups was <200 points, far below the authors’ predefined threshold for a clinically meaningful result.
- Change in body weight favored the continuous-infusion and high-dose groups, as might be expected.
- The high-dose group had a significantly higher proportion of patients with creatinine increases of >0.3 mg/dL than did the low-dose group (23% vs. 14%; P=0.04). Again, we should be careful about interpreting the statistical significance of this, but an absolute difference of 9% for a potent risk factor like worsening renal function is hard to ignore and does raise concerns.
5. The recommendation by the editorialist. The editorialist came out with a strong endorsement for the high-dose regimen, arguing that it reduces dyspnea without worsening renal function. My interpretation is a bit different, but I tend to require better evidence to justify using more of a medication. Here is where the journal club should get interesting: What do you think are the implications of this study? Do you agree with the editorialist that it should change practice? Was the trial designed to address the question you have about how to use diuretics? If not, what would you have done differently? How should the guidelines incorporate this new information, if at all?
I look forward to your thoughts.
For more on the DOSE study, check out Anju Nohria’s Voices blog.
March 2nd, 2011
Questioning the DOSE
Anju Nohria, MD
Although widely used for decades, the best way to use loop diuretics in patients with acute decompensated heart failure (ADHF) has never been well studied. The Diuretic Optimization Strategies Evaluation (DOSE) study, published in the New England Journal of Medicine, randomized 308 ADHF patients to a bolus every 12 hours or a continuous infusion of furosemide at either a high or low dose. No significant differences were observed in either patient symptoms or the change in creatine from baseline to 72 hours. In an accompanying editorial, Gregg Fonarow writes that the study “has not solved the problem of the poor prognosis for patients hospitalized with acute decompensated heart failure, nor has it modified the substantial expenditures for this disease.” However, Fonarow argues that the study introduces “the new concept of comparative-effectiveness studies into the field of heart-failure research.”
As a heart-failure clinician, these are some of my thoughts about the DOSE trial:
What did I like about DOSE?
In conducting DOSE, the NIH-sponsored Heart Failure Consortium has taken an important step back to evaluate age-old, evidence-devoid practice patterns, instead of focusing solely on novel therapies.
What did DOSE show?
The results suggest that high-dose, compared to low-dose, diuretics improve patient symptoms, and increase net diuresis and weight loss within 72 hours of hospitalization. However, they do so at the expense of a greater proportion of patients developing worsening renal function during their hospital stay. While the trial was not powered to look for differences in re-admission or mortality, high-dose diuretics — despite their early benefit — were not associated with a decrease in median length of stay or a decrease in the rate of death or re-hospitalization within 6 months, compared to a low-dose strategy.
What did DOSE claim to show, but didn’t?
The results suggested that there was no difference in 72-hour or 6-month outcomes between the bolus and continuous infusion strategies. However, patients randomized to the bolus strategy received substantially higher doses of diuretics than those randomized to the continuous infusion strategy (median dose: 592 mg vs. 480 mg, p=0.06). Therefore, before we can conclude that continuous infusion is no better than bolus dosing — shouldn’t we compare the bolus and continuous strategies within the low- and high-dose groups? Unfortunately, the trial was not adequately powered to conduct these subset analyses.
What would I have liked to know from DOSE?
I wish the Heart Failure consortium had powered the study to look for differences in heart-failure death or re-hospitalization between the different diuretic strategies. The plethora of prior literature suggesting that high-dose diuretics lead to bad outcomes, both because of and irrespective of worsening renal function, has led to the systematic under-treatment of patients with ADHF. Even in DOSE, less than 20% of patients were free from congestion after 72 hours of treatment in the hospital. While we do not know the proportion of patients who were free from congestion by the time of discharge, it is safe to assume that the majority were still “wet” given that the median length of stay was approximately 5 days in each treatment group. We know that 43% of patients were either dead, re-hospitalized, or presented to the Emergency Department within 60 days of randomization. What we don’t know is whether this was because they were discharged prematurely, because there truly was no difference between the different diuretic strategies, or whether the initial benefit gained with high-dose diuretics was negated by the higher incidence of worsening renal function.
So, in the end, is DOSE really going to change how we give diuretics? As it stands, all that DOSE tells us is that in a small trial of 308 patients, the way you administer diuretics has no impact on patient outcomes. In my opinion, the failure to power DOSE to see a difference in a conclusive hard end-point will make it a valiant research attempt that has virtually no impact on clinical practice.
For more on the DOSE study, check out Harlan Krumholz’s journal club.
March 2nd, 2011
FDA Finds No Increased Risk For MI With Abacavir
Larry Husten, PHD
An ongoing safety review by the FDA of the antiviral medication abacavir found no evidence for an increased risk for MI associated with the drug. The FDA said an increased risk for MI with abacavir had been seen in several observational studies and one randomized controlled trial (RCT), but not in other RCTs or in the drug’s safety database. The FDA therefore conducted a meta-analysis of 26 RCTs and found no evidence for an increased risk for MI associated with the drug.
March 1st, 2011
CV Device Trials Still Fail To Include More Women
Larry Husten, PHD
Women continue to be significantly underrepresented in trials of cardiovascular devices, according to a study published in Circulation: Cardiovascular Quality and Outcomes. Sanket Dhruva and colleagues performed a systematic review of the PMA applications for 78 high-risk cardiovascular medical devices submitted to the FDA from 2000 to 2007.
Despite repeated attempts to call attention to the issue and institute changes by various government and medical organizations like the NIH, FDA, and the AMA, the investigators reported that most studies failed to include enough women to adequately assess the safety and efficacy of the devices in women. Where the information on gender distribution was available, men composed two-thirds of the study populations, with no increase in the proportion of women observed over time.
“Women and men differ in their size, bleeding tendencies, and other factors that are directly relevant to how the devices will work,” said Rita Redberg, the senior author of the study, in an AHA press release. “We found no encouraging trends. Failure to include women in clinical trials has been a big problem for a long time and it isn’t improving, so further action is needed.”
March 1st, 2011
CV Patients Without Hypertension Benefit From Antihypertensive Therapy
Larry Husten, PHD
A new study suggests that patients with CV disease who do not have hypertension may nevertheless benefit from antihypertensive therapy. In a study published in JAMA, Angela Thompson and colleagues performed a meta-analysis of 25 trials including 64,162 patients with CV disease or a risk factor equivalent and without hypertension. Compared to controls, patients who received antihypertensive therapy had
- a 23% reduction in risk of stroke,
- a 29% reduction in risk of CHF events,
- a 15% reduction in risk of a combination of CVD events,
- and a 13% reduction in risk of all-cause mortality.
In an accompanying editorial, Hector Ventura and Carl Lavie write that “the clinical importance of this study is clear: pharmacological intervention in patients with CVD and blood pressure levels less than 140/90 mm Hg is associated with a decreased risk of cardiovascular morbidity and mortality.” However, they point out that since “many patients could potentially begin taking medications at young ages and for many years to prevent cardiovascular events, even modest costs and adverse effects need to be considered.”
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