October 5th, 2010
Has Subgroup Exuberance Led to Misleading Advertising?
CardioExchange Editors, Staff
Harlan Krumholz’s latest Journal Club installment, which focuses on subgroup analyses from TRITON-TIMI 38, has generated great comments, including Harlan’s own new observation about how these subgroup data are being misused in advertising. Read what he has to say and share your own thoughts here.
So I am perusing my current issue of JACC and I notice that there is an ad for Effient (prasugrel) that is all about the subgroups in TRITON. And the language is misleading in my opinion. They tout the reductions in thrombotic CV events in diabetes subgroups and state, “The greater reduction in the primary composite endpoint in patients with diabetes treated with Effient plus ASA compared with Plavix plus ASA was consistent with those observed in the overall UA/NSTEMI and STEMI populations.” By saying the ‘greater reduction’ there is the suggestion that there is a signal of great benefit – but the rest of the sentence concedes that the effect in diabetics is no different than non-diabetics. So why the emphasis on the greater reduction – many who are not familiar with the study might think the drug is more effective in diabetics – which the trial does not indicate. And there is more. For bleeding they present a beautiful figure that shows that Effient has a higher risk of non-CABG related major bleeding in the entire study group (2.2% vs 1.7%) — beside it is another bar graph suggesting that the rates in diabetes are similar (2.2% vs 2.3%) – that would be great except that there is no evidence that the bleeding risk in diabetics is different than non-diabetics. And in small font – very small font – under the figures, it says, “P value not provided because the trial was not designed to prospectively evaluate bleeding differences in subgroups.” I wish that were in a larger font. Take a look at the ad and see what you think.
To comment, join in the discussion on the original post here.
October 5th, 2010
Compression-Only CPR Gains More Support
Larry Husten, PHD
There’s more evidence to encourage widespread adoption of chest compression-only CPR by nonmedical responders. Bentley Bobrow and colleagues analyzed data from 4415 adults with out-of-hospital cardiac arrest who did not receive CPR from a medical professional. After adjusting for baseline differences, the survival rate did not differ between people who received conventional CPR from lay rescuers and those who received no CPR at all. By contrast, people who received lay-rescue compression-only CPR had a significantly better chance of survival compared with those who received no CPR and those who received conventional CPR. In addition, in their report in the Journal of the American Medical Association, the investigators report that from 2005 to 2009, lay-rescue CPR increased significantly over time, and that the proportion of CPR that utilized compression-only CPR increased from 20% to 76%. Overall survival rose from 3.7% in 2005 to 9.8% in 2009.
In an accompanying editorial, David Cone notes that standard CPR and compression-only CPR are considered equivalent by the AHA and that in guidelines expected later this year, compression-only CPR will likely “continue to be deemed at least equivalent to standard CPR, if not superior, for nonmedical bystanders.”
October 4th, 2010
Gene Expression Test Brings Modest Improvement to Patient Classification
Larry Husten, PHD
A gene expression test can improve the prediction of CAD but may not be clinically useful, according to results of the Personalized Risk Evaluation and Diagnosis in the Coronary Tree (PREDICT) study published in the Annals of Internal Medicine. The PREDICT investigators, led by Eric Topol, evaluated a gene expression test based on 23 genes associated with CAD in 526 nondiabetic patients scheduled for coronary angiography. The investigators concluded that the test provided “statistically significant but modest improvement in classification of patient CAD status compared with clinical factors or noninvasive imaging.”
In an accompanying editorial, Donna Arnett writes that the study “is an initial proof-of-concept for the potential use of genetic risk scores in the context of cardiovascular disease” but that “it does not fulfill the tough evidentiary standards that modern clinicians should demand.”
October 4th, 2010
Study Finds Deep Ties Between Sleep and Weight Loss
Larry Husten, PHD
A good night’s sleep might be a key to losing weight. In a crossover study among 10 overweight people, Arlet Nedeltcheva and colleagues compared the effects of 2 weeks of dieting with 8.5 or 5.5 hours of sleep each night. They found that during the sleep curtailment period, weight loss came more from lean body mass, fat oxidation was reduced, and hunger levels and circulating gherlin levels were higher.
In an accompanying editorial in the Annals of Internal Medicine, Shahrad Taheri and Emmanuel Mignot write that the study provides “insight on why sleep deprivation interferes with the achievement and maintenance of healthy weight” and agree with the authors that “adequate sleep might be an important factor in successful weight loss, and perhaps sleep should be included as part of the lifestyle package that traditionally has focused on diet and exercise.”
October 4th, 2010
Widespread Routine Use of Closure Devices Not Recommended
Larry Husten, PHD
Arterial closure devices (ACDs) “have the potential to improve patient comfort,” but the current evidence isn’t sufficient to support routine use after cardiac catheterization, according to a scientific statement from the AHA published in Circulation. Led by Manesh Patel, the committee analyzed the data and concluded that although it is “reasonable” to consider using an ACD after catheterization, “the available evidence is limited to specific patient populations, often studied in nonrandomized fashion, without methodological follow-up and standardized clinical outcomes. This limits the widespread routine use of these devices in clinical practice.”
October 4th, 2010
Consensus Statement Highlights Urgency of Treating Hypertension in Blacks
Larry Husten, PHD
Hypertension in blacks should be treated earlier and more aggressively, according to an update of the International Society on Hypertension in Blacks (ISHB) consensus statement published in Hypertension. The update lowers the threshold for treatment and recommends that:
- Lifestyle changes be initiated in African-Americans when blood pressure is at or above 115/75 mm Hg.
- Drug therapy be initiated when blood pressure is at or above 135/85 mm Hg for primary prevention and 130/80 mm Hg for secondary prevention.
- Physicians employ combination drug therapy earlier than previously (the update makes specific recommendations for choosing drugs with numerous options for individualizing therapy).
“Evidence from several recently completed studies converged to convince our committee that we were waiting a little bit too long to start treating hypertension in African-Americans,” said the lead author of the statement, John Flack, in a press release from the AHA. “The majority of patients of any race, and certainly African-Americans, are going to need more than one drug to be consistently controlled below their goal. The debate in the medical community over which single drug is best overwhelms the most pressing question: Which drugs work best together?”
October 1st, 2010
A Case of Exuberance About a Subgroup in a Clinical Trial
Harlan M. Krumholz, MD, SM
In many clinical trials, researchers investigate whether an overall effect of an intervention is consistent across various subgroups, as I discussed in this Journal Club Series last week. Such subgroup analyses require assessment of what is called an interaction — that is, whether the effect in one group differs from that in another. Do the benefits differ, for example, between older and younger patients — or between men and women? That may sound like an easy issue to explore, but penetrating it demands an appetite for methodological nuance. Are you ready? Here we go . . .
The basic principle of subgroup analysis is that before you assess the effect of an intervention in each subgroup of interest, you must assess whether there is strong evidence of statistically meaningful differences among the subgroups. If older patients and younger patients benefit similarly from a drug, for example, there is no reason to look at one group alone, because the overall trial outcomes apply to both groups.
This week, I focus specifically on a study showing that bleeding risk was significantly greater with prasugrel than with clopidogrel in ACS patients scheduled for PCI. The researchers published a subsequent article focusing just on the patients with ST-segment–elevation MI (STEMI) and concluded that there was no excess risk for bleeding in that subgroup, even though the difference in that risk between STEMI and unstable angina/non–STEMI (UA/NSTEMI) patients was not significant. These studies are instructive for thinking about how to interpret subgroup analyses accurately.
Results Recap
The articles are a 2007 NEJM paper and a 2009 Lancet paper from the industry-funded TRITON-TIMI 38 trial, in which 13,608 patients with moderate-to-high risk ACS who were scheduled for PCI were randomized to receive prasugrel or clopidogrel. Incidence of the primary endpoint — death from cardiovascular causes, nonfatal MI, or nonfatal stroke at 15 months — was significantly lower in the prasugrel group than in the clopidogrel group (9.9% vs. 12.1%), mostly because of fewer nonfatal MIs. However, the incidences of major and life-threatening bleeding were significantly higher with prasugrel. In a 2009 NEJM perspective piece, an FDA official characterized the data as follows:
“For each 1000 patients who were given prasugrel instead of clopidogrel, 24 end-point events were prevented — 21 nonfatal myocardial infarctions and 3 cardiovascular deaths. (The rate of stroke was essentially the same with either drug.) The cost was 10 excess major or minor bleeding events, 2 of which were fatal.”
What the Authors Analyzed
It’s important to emphasize that this trial reported analyses for 7 subgroups on the primary outcome, as well as several secondary outcomes including safety outcomes — quite a few comparisons in all. When there are multiple subgroup comparisons, P values for analyses beyond the primary endpoint must be adjusted to more stringent levels than the usual P<0.05, in order to account for the likelihood that the differences may be due to chance. A common approach is to divide 0.05 by the number of tests performed, but there are other ways to do this adjustment.
When the NEJM findings were published, the authors reported the significant difference between prasugrel and clopidogrel in the overall cohort and reported no evidence of a difference (interaction) between treatment group and type of MI. They then looked specifically at the primary outcome in the UA/NSTEMI and STEMI subgroups and found an advantage of prasugrel, at the P<0.05 level of significance, in each.
In their 2009 Lancet article, the authors focused only on the STEMI subgroup. They declared the primary-endpoint advantage of prasugrel in STEMI patients, reiterating the finding earlier reported in the NEJM. So far, so good: There was no interaction reported in the NEJM paper, and the Lancet paper said the same thing — the result is similar. It’s important to note that even if the effect had been reported as nonsignificant in the Lancet paper, the drug should not be considered ineffective in STEMI patients. Given that the interaction was negative, the efficacy of the intervention in the underpowered STEMI subgroup should be considered the same as it was in the overall cohort. In short, we have no evidence of an intervention-related difference between STEMI and UA/NSTEMI patients.
The authors also looked at safety endpoints. Specifically, they reported in the Lancet that the type of MI did not influence the excess risk for bleeding conferred by prasugrel (P=0.4). Therefore, the interaction between the bleeding risk with prasugrel and type of MI was negative (i.e., no evidence of heterogeneity for type of MI). However, the authors went on to assess the STEMI group alone and did not find a significantly increased risk for bleeding. They write, “TIMI major bleeding unrelated to CABG surgery was similar in the prasugrel and clopidogrel groups at both 30 days and 15 months.” This statement suggests that unlike patients with UA/NSTEMI, those with STEMI are not at increased risk for bleeding.
The problem is twofold: (1) the interaction, as noted, was not significant; and (2) the prasugrel versus clopidogrel hazard ratio for TIMI major bleeding unrelated to CABG was hardly reassuring (HR, 1.11; 95% CI, 0.70–1.77). That HR is not statistically significant, but it is in the direction of harm, and a 77% higher risk with prasugrel cannot be excluded. The best inference is that the excess bleeding risk in the STEMI subgroup is no different than that reported for the overall cohort.
How the Authors Interpreted Their Analyses
The authors conclude their Lancet abstract with this sentence: “In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.” And they end the entire Lancet article with this sentence: “Our findings suggest that prasugrel is an especially attractive alternative to clopidogrel to support PCI in the course of management of patients with STEMI.”
At the conclusion of your journal club, participants can decide whether the evidence from these articles is strong enough to say that STEMI patients gain a particular benefit from prasugrel. For now, please share your perspective with your colleagues here on CardioExchange.
October 1st, 2010
Chronic Kidney Disease and Cardiovascular Risk
Larry Husten, PHD
People with early-stage chronic kidney disease are at elevated risk for cardiovascular disease, according to a new study published in BMJ. Researchers from the U.K. and Iceland followed 17,000 adults in Reykjavik for a median of 24 years and found that people with chronic kidney disease at baseline had significantly elevated risk for cardiovascular events, and that adding information about chronic kidney disease to conventional risk factors improved prognostication. However, the incremental gain was lower than that provided by diabetes or smoking.
The U.K. and Icelandic authors acknowledge that “although plausible mechanisms have been proposed to suggest that impaired kidney function may itself be a causal factor in coronary heart disease, the possibility remains that chronic kidney disease is chiefly a marker of unfavourable cardiovascular risk profiles.”
In a second study appearing in BMJ, U.S. and Chinese investigators performed a meta-analysis of 284,672 participants in 33 prospective studies and found that low baseline eGFR was independently related to increased stroke risk. The risk was elevated more in Asian subjects.
In an accompanying editorial, Vlado Perkovic and Alan Cass write that the “evidence suggests that the presence of chronic kidney disease (either reduced eGFR or albuminuria, but especially both) should act as a ‘red flag’ that triggers cardiovascular risk assessment and implementation of appropriate preventive strategies.”
September 30th, 2010
Don’t Take My Fun Away
John Mandrola, MD, FACC
John Mandrola is a cardiac electrophysiologist who blogs on matters medical and general at Dr John M. In a recent post, he celebrates his enduring sense that doctoring is still a great job.
———
“Did you sign those three consents?”
“This patient needs a short form; your office letter was 30 days and 1 hour ago.” (just over the legal limit)
“The insurance ‘people’ in area code (***) denied the stress test.”
“Mr Smith’s son, an alternative medicine specialist in California, wants a phone call to discuss herbal therapy of AF instead of ablation.”
To these and the infinite number of similar hassles, I have been responding with a new plea, “Please don’t take the fun out of doctoring.” Saying it out loud, like a childhood prayer, reminds me of the truth: that doctoring is, still, a really great job.
This week, two unusual things happened to me that reinforced this truth.
First, an internist called me to say there was a nearly 100-year-old who had heart block requiring a pacemaker. She is an enlightened doctor and knew my gut reaction, so she quickly added, “This patient is a good 95; we’ve already been there.” And then she said one more thing. “I have a fourth-year medical student who is rotating with me . . . can she come watch? I have no idea how a pacemaker is installed, maybe you could show her, and she could tell me.”
We are only a scant few miles from the university, and yet a Berlin-wall–like barrier seems to exist between the private world and the university. Every once in while, though, a “younger” escapes on some elective rotation. They are sent out into the deep, dark forest of the private practice world. Such escapees are always young, and as time passes, they appear even younger.
To us nonacademics, there is nothing quite like having a motivated, youthful escapee to listen to your show-and-tell. The internist’s student had never seen an EP lab, a cephalic vein isolated, a simple peel-away sheath, or a pacemaker lead. Who knew that basic physics 101– the flow of electrons – would apply so directly to patient care?
“While she’s here, it wouldn’t hurt to show her some more stuff,” I thought. Then there was a cardioversion. So simple to us, so ‘shocking’ to the fourth-year medical student, who jumped a little with the patient.
“Ok, it’s time to go, I know you need to get back to your primary care rotation.” But on the way out, the young escapee peered into the interventional lab, as if to say, “what’s going on in there?” So we went in to see the “squishers.” I am not sure what impressed her more – the visual miracle of a 90% blockage being reduced to nothing or the fact that the doctor was passionately chastising the ‘versed-ized’ patient on the dangers of persistent smoking while he squished.
“Dr Mandrola,” whispered a cath lab nurse, “I think I like having medical students around, too.”
The second occurrence was late on a Friday, as I was rushing through the usual Friday-afternoon feast of documentation. He was interviewing for a job, and I was to discuss our medical community. Just out of training at a major university in a major city, he was young, with small children and a wife who was a doctor as well. He asked about our medical community and whether I was happy.
I started to talk, and a surprising thing happened. Only the good things seemed to come to mind. Not that I was trying to bamboozle him, but the ‘cubicle-doctors,’ the forms, the pharmacy requests, and even the covert rationing of care were all involuntarily suppressed. The joy of doctoring came to the fore. Truths like: We have hard-working, good-hearted and well-educated colleagues (nurses and doctors) to work with, we have the support of a benevolent (albeit increasingly stressed) hospital administration, and, mostly, we have many grateful patients.
I stayed and talked later than I should have. Because it felt good to reflect on what is still right with the system. My academic colleagues interview incoming prospective faculty and students frequently, and as part of their charge, they get to show stuff to youngers every day. I’m envious of this, for sure. Such opportunities for reflection on what is so good about our profession are less common on the speedy private-practice treadmill. So when they occur they should be savored. Writing them down helps me remember.
Grin.
September 29th, 2010
How Are You Managing Co-Morbid Conditions?
Joseph S. Ross, MD, MHS
Some of you may remember a 2005 paper in JAMA, in which relevant clinical practice guidelines were applied to a hypothetical 79-year-old woman. This woman had multiple co-morbid conditions, otherwise known as multimorbidity, including COPD, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis. The authors surmised that, if guideline-directed care were followed, this hypothetical patient would be prescribed at least 12 medications (costing at least $406/month) and would require a modified diet and exercise interventions.
Since this paper was published, we better recognize the importance and challenge of managing mulitmorbidity when making recommendations for treatment and prevention to patients in our practices.
However, no easy fixes to the problem have been identified.
I raise this issue here since all physicians, particularly general internists and preventive cardiologists, are frequently making a multitude of treatment and prevention decisions for patients, for problems within and outside of their clinical specialty.
Another more recently published paper in Archives of Internal Medicine is also worth considering. In this study, the authors interviewed primary care physicians (PCPs) about how they make treatment decisions for older patients with multiple chronic diseases. They identified 3 important challenges that all physicians face as when attempting to improve practice.
1. These PCPs were concerned about their patients’ ability to adhere to complex guideline-directed care and uniformly supported the need to tailor care to individual patients. But beyond this certainty, opinions diverged. Some believed that the benefits of guideline-directed care outweigh the harms, while others believed the opposite to be true, and still others thought there wasn’t sufficient data to support either position.
2. PCPs used varying strategies to balance risks and benefits while adhering to complex guideline-directed care. Some tried to prioritize certain clinical problems; for example, focusing on cardiovascular disease no matter what other conditions the patient had. Others stratified risk for individual diseases and focused treatment accordingly, such as focusing on fall risk, as opposed to cardiovascular risk, for an 85-year-old patient, but reversing the focus for a 70-year-old patient. Still others modified treatment in anticipation of adverse effects.
3. Many PCPs described conflicts between what they wanted to do for the patient and what the patient wanted.
What do you think? Is there a “right way” to manage patients with multimorbidity?
How are you balancing the risks and benefits of providing guideline-directed care in practice?
As general internists or preventive cardiologists, do you prioritize treating cardiovascular disease or tailor care in other ways?
Have you found any strategies to be helpful with patients or any tricks to facilitating care?
How do those of you who are interventionalists consider multimoribidity when making treatment decisions?
NEJM Journal Watch — Recent Cardiology Articles- Optimal Management of NSTEMI in Older Adults: A Meta-Analysis
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- Should Patients Take Once-Daily Antihypertensive Drugs in the Morning or the Evening?
- Exercise as Medicine for Preventing Colon Cancer Recurrence