September 18th, 2013
Both Overuse and Underuse Explain Disparities in Coronary Revascularization
Larry Husten, PHD
A new study finds that groups who have often been found to receive less medical care — non-whites, women, and people without private insurance or who are from urban and rural areas — are less likely to undergo coronary revascularization. But the same study finds that this disparity may be in no small part due to the fact that these same groups are less likely to receive inappropriate procedures. The study, published online in the Journal of the American College of Cardiology, suggests, therefore, that the apparent underuse of healthcare in some groups may be partly counterbalanced by overuse in other groups.
Applying appropriate use criteria (AUC) to data from the National Cardiovascular Data Registry (NCDR), Paul Chan and colleagues found, consistent with previous studies, that 12.2% of the more than 211,000 non-acute PCIs performed between July 2009 and March 2011 were inappropriate. Digging deeper into the data they found:
- Men were more likely than women to receive an inappropriate PCI (adjusted odds ratio 1.08, CI 1.05-1.11, p < 0.001)
- Whites were more likely than non-whites to receive an inappropriate PCI (OR 1.09, CI 1.05-1.14, p < 0.001)
- Patients with Medicare were less likely than those with private insurance to receive an inappropriate PCI (OR 0.85, CI 0.83-0.88)
- Patients with other public insurance were less likely than those with private insurance to receive an inappropriate PCI (OR 0.78, CI 0.73-0.83)
- Patients with no insurance were less likely than those with private insurance to receive an inappropriate PCI (OR 0.56, CI 0.50-0.61)
- Patients treated at rural hospitals were less likely than those at urban hospitals to receive an inappropriate PCI (OR 0.92, CI 0.88-0.96)
- Patients treated at suburban hospitals were more likely than those at urban hospitals to receive an inappropriate PCI (OR 1.10, CI 1.07-1.13)
In an accompanying editorial, Karen Joynt points out the “flip side of poor quality” in which the “patterns of overuse of PCI were diametrically opposed to prior research on patterns of underuse.” She writes that it is quite likely that “there is concurrent underuse and overuse” of PCI, both of which need to be addressed: “Both sides of the quality paradigm – underuse and overuse – must be together at the forefront of our quality improvement efforts.”
In an interview with CardioExchange, Chan said that although “we have come a long way in ensuring that care is delivered equitably and thoughtfully in the US… there is no doubt that underuse in certain populations remains a persistent and huge problem. For policymakers… it highlights the importance of thinking about differences in treatment in a more complex way– as due to underuse and also potential overuse. Therefore, the goal may be to narrow the gap in vulnerable populations in instances where treatment has clearly established benefit rather than assuming that the measured difference is entirely due to a disparity in care.” Chan also said the paper was consistent with the hypothesis that patients for whom physicians are paid more are more likely to undergo inappropriate procedures.
In a statement issued by the American College of Cardiology, former ACC president Ralph Brindis said that “it is important to note that the Appropriate Use Criteria terminology has been updated since the creation of Dr. Chan’s manuscript from ‘Inappropriate’ to ‘Rarely Appropriate.’ The new terminology acknowledges that in certain rare cases when the patient’s individual circumstances are considered as part of a shared decision-making process, stents in this category would be considered ‘Appropriate.'” He acknowledged that “at present, we are better equipped to measure ‘Rarely Appropriate’ or overuse of care than determining the underuse of care. The American College of Cardiology is very concerned about racial and socioeconomic disparities in underuse of care.”
Paul Chan answers CardioExchange’s questions about the study here. (Note: Comments on this news story are closed; we welcome your comments at the Chan interview.)
September 18th, 2013
Younger Women with ACS Less Likely to Have Chest Pain
Larry Husten, PHD
Younger women with an acute coronary syndrome are slightly less likely than men to present with the classic symptom of chest pain, according to a new study published in JAMA Internal Medicine. In recent years there has been a growing understanding that women with ACS are less likely to have chest pain and, partly as a result, often fail to receive a correct diagnosis in the emergency department. However, there has only been limited data on whether this pattern is also true for younger women.
Nadia Khan and colleagues prospectively analyzed data from more than 1000 ACS patients 55 years of age or younger — 30% of whom were women — participating in the GENESIS PRAXY study. When compared with older cohorts in previous studies, patients in GENESIS PRAXY were more likely to have chest pain, but even in these younger patients, women were less likely to have chest pain than men (19% of women versus 13.7% for men, p = 0.03). In addition, women were more likely than men to have a non-ST-segment elevation myocardial infarction (37.5% vs 30.7%; p = 0.03). Upon multivariate analysis, women and patients with tachycardia were less likely to have chest pain. The absence of chest pain did not herald any change in the type or severity of the ACS.
The investigators said that there was no clear reason for the lower prevalence of chest pain in younger patients and that there is “no discernible pattern of non-chest pain symptoms” that can be used to help identify ACS in these patients. They conclude:
Strategies that explicitly incorporate standardized assessment of common non–chest pain symptoms or signs, such as weakness, shortness of breath, or tachycardia in emergency departments also need to be evaluated.
In an accompanying editorial, Akintunde Akinkuolie and Samia Mora write that the study “extends the prior literature by demonstrating that sex-specific differences in ACS presentation occur earlier in life.” They acknowledge that “diagnosis of any disease with a lower prevalence but higher mortality, such as coronary artery disease in younger women, is more challenging” and recommend that public health messages should “target both men and women regarding ACS symptom presentation with or without chest pain so as to encourage earlier and more widespread access to appropriate and lifesaving care.”
September 18th, 2013
Is Edoxaban the Most Promising of the Novel Anticoagulants?
Samuel Goldhaber, MD
CardioExchange’s John Ryan asks Samuel Z. Goldhaber for his perspective on the Hokusai-VTE randomized trial comparing edoxaban and warfarin in patients with symptomatic venous thromboembolism. For a summary of the findings, see CardioExchange’s news coverage of the trial.
John Ryan: Why should clinicians pay attention to this study?
Goldhaber: Hokusai-VTE is breathtaking in its magnitude and scope — the largest ever randomized trial of anticoagulation for symptomatic deep-vein thrombosis (DVT) and pulmonary embolism (PE). It enrolled 8240 patients, including 3319 with PE. About 1000 of the patients with PE underwent more-detailed chest CT classification to determine whether they had right ventricular dysfunction, defined as an RV-to-LV diameter ratio >0.9. One third of PE patients met this criterion. RV dysfunction was also determined according to elevation of the biomarker NT-proBNP, measured in about 90% of PE patients and elevated in 28%.
The trial permitted downward adjustment of the standard 60-mg once-daily dose of edoxaban to 30 mg once daily for patients with impaired renal function or low body weight. Edoxaban’s safety was superior to that of warfarin, with 19% fewer major or clinically relevant nonmajor bleeding events. Most eye-catching were the results in PE patients with RV dysfunction (according to elevated NT-ProBNP). In this prespecified subgroup, edoxaban nearly halved the rate of recurrent VTE (from 6.2% with warfarin to 3.3%), demonstrating superior efficacy to warfarin.
John Ryan: Where do this trial and edoxaban fit on the entire spectrum of available anticoagulants?
Goldhaber: Edoxaban (Hokusai-VTE) joins the ranks of dabigatran (RE-COVER), rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE), and apixaban (AMPLIFY) as a novel oral anticoagulant whose efficacy is noninferior to warfarin for preventing recurrent VTE and, like apixaban, superior to warfarin for the safety endpoint of major and clinically relevant nonmajor bleeding. But edoxaban goes a step further in efficacy: It is the first anticoagulant to demonstrate superiority for efficacy in any prespecified subgroup. The fact that edoxaban nearly halved the rate of recurrent VTE in patients with PE and RV dysfunction raises the question of whether edoxaban could be used without adjunctive systemic or pharmacomechanical thrombolysis for patients at the “healthier end” of the wide clinical spectrum of submassive PE. Hokusai-VTE is also the only trial of one of the four novel anticoagulant VTE drugs to test dose reduction for patients with impaired kidney function or low body weight. Low-dose edoxaban performed as well as standard-dose edoxaban with respect to efficacy and safety.
JOIN THE DISCUSSION
In light of the findings from Hokusai-VTE, how do you perceive edoxaban in the panoply of novel anticoagulants?
September 17th, 2013
How Well Does Hypertensive Retinopathy Predict Stroke?
Mohammad Kamran Ikram, MD PhD
CardioExchange’s editor-in-chief Harlan Krumholz interviewed Mohammad Kamran Ikram about his research group’s investigation of the value of hypertensive retinopathy in predicting the long-term risk for stroke in patients with hypertension. The study is published in the journal Hypertension.
THE STUDY
Researchers enrolled 2907 patients with hypertension (age 50 to 73 on initial examination) from the Atherosclerosis Risk in Communities study. All had gradable retinal photographs; no history of diabetes mellitus, stroke, or coronary heart disease at baseline; and available data on incident stroke. Mean follow-up was 13 years. After adjustment for potentially confounding risk factors, participants with moderate hypertensive retinopathy were significantly more likely than those with no retinopathy to experience stroke (hazard ratio, 2.37; 95% CI, 1.39–4.02). In participants with well-controlled hypertension while on treatment, mild and moderate hypertensive retinopathy were each associated with significantly increased risk for cerebral infarction.
THE INTERVIEW
Harlan Krumholz: You show that hypertensive retinopathy has prognostic importance beyond blood pressure. Please explain what you think the underlying mechanism might be.
Ikram: High blood pressure is one of the most important risk factors for stroke (caused by a blood clot in the brain), but predicting exactly which patients with hypertension will develop a stroke is still not possible. A simple blood pressure measurement cannot elucidate the underlying mechanisms, because the blood pressure we measure is the net result of many processes, including functional and structural changes. However, the presence of “hypertensive retinopathy” gives us specific information on structural damage to the small blood vessels.
Harlan Krumholz: You depend on retinal photographs. Might a routine retinal examination produce the same information?
Ikram: Routine retinal examination using fundoscopy has been shown to have low inter- and intrarater reliability. Hence, there is a need to obtain standardized images of the retina, which can then be evaluated by experienced graders. In our study, we tried to streamline this process by using a simplified Hypertensive Retinopathy Grading system. The first step was to demonstrate the link between retinal features and the development of stroke using a standardized method of assessing the retina. Future work must determine whether routine examination using fundoscopy provides the same sort of information about risk for stroke.
Harlan Krumholz: Should an evaluation for hypertensive retinopathy be part of every exam? What should we do if we find it in the absence of uncontrolled hypertension?
Ikram: It is too early to recommend changes in clinical practice. Other studies need to confirm our findings and show that retinal imaging provides additional information on predicting the risk for stroke in people with high blood pressure.
JOIN THE DISCUSSION
How useful do you think retinal photographic assessment of hypertensive retinopathy will become in predicting hypertensive patients’ risk for stroke?
September 16th, 2013
Intense Lifestyle Changes May Lengthen Telomeres
Larry Husten, PHD
A very small pilot study offers early evidence that a program of comprehensive lifestyle changes increases telomere length. Telomeres, which have been compared to the plastic caps that prevent shoelaces from unravelling, help protect chromosomes. Telomere length is closely correlated to cellular aging: as we age the telomeres in our cells grow shorter. The new study, published online in Lancet Oncology, is one of the first studies to test whether the Nobel-prize winning research into telomeres has a role to play in assessing the health of humans in typical clinical situations.The first author of the new paper is Dean Ornish, whose career has been devoted to demonstrating the benefits of a comprehensive lifestyle program consisting of radical changes in diet and exercise, accompanied by stress management and social support. The senior author of the paper is Elizabeth Blackburn, who won the Nobel Prize for her discovery of telomeres and their significance. In the paper, Ornish and colleagues report on a long-term followup study in a small group of people with low-risk prostate cancer who agreed to follow Ornish’s rigorous program.
After 5 years, telomere length increased in this group and decreased in a group of matched controls. Adherence to the lifestyle program varied among the participants, and some members of the control group made lifestyle changes on their own. The investigators reported that change in telomere length was significantly related to the degree of lifestyle change regardless of the study group. Further, as expected, telomere shortening was independently predicted by age, but the effect of the lifestyle program was independent of age and worked in the opposite direction.
In 2008, the same group reported the 3-month results of their study showing an increase in telomerase activity in the treatment group. (Telomerase is the enzyme that repairs telomeres and is associated with telomere lengthening.) Surprisingly, however, the 5-year results found no significant differences in telomerase activity between the two groups. Prostate-specific antigen values, a measure of prostate cancer activity, also did not differ significantly between the two groups.
The authors offered the following interpretation of their study:
“Our findings are consistent with those of earlier studies, but to our knowledge this is the first study of any intervention that has shown a significant change in relative telomere length in human immune-system cells over time when compared with a non-intervention group. We noted a correlation between the degree of positive lifestyle change and increase in telomere length when all participants were assessed together, which supports the internal validity of this study. Although our sample size was small and all participants had early-stage cancer with low risk of metastasis, we believe large, randomized trials to test the validity and applicability of our results are warranted.”
In an email interview, Ornish said:
“The prospect of beginning to reverse aging on a cellular level is an important finding that may be of great interest to your readers who, I hope, will feel inspired and empowered by them. Our genes are not our fate. And now that I’ve just turned 60, it has personal meaning as well!
…
This is the same lifestyle intervention that we showed in earlier randomized, controlled trials may stop or reverse the progression of coronary heart disease and early-stage prostate cancer, as well as improve gene expression in over 500 genes in just three months. In these earlier studies, we also found a dose-response relationship between the degree of lifestyle change and the degree of improvement in a variety of metrics — the more you change your lifestyle, the more you improve — at any age.”
Donna Arnett, the president of the American Heart Association, said that the study was “interesting” and “fascinating” but pointed out that it was a very small pilot study with only 10 people in the intervention group. “The fact that they could increase telomere length is impressive,” she said. Interventions that increase telomere length are worth further study, but it will be extremely difficult to prove a link between the effect on telomeres of an intervention and an improvement in outcomes. She also noted that patients in the treatment group were “clearly a very motivated group” who had good adherence to the program. For “people with time and motivation this may be feasible… for other people this might be a challenge.”
September 16th, 2013
Selections from Richard Lehman’s Literature Review: September 16th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 29 Aug-12 Sep 2013 Vol 369
Oral Apixaban for the Treatment of Acute VTE (pg. 799): When comparing a new fixed-dose anticoagulant with conventional warfarin based anticoagulation, what do you look for? Thrombotic events, death, major bleeding? Yes, certainly. But what makes the comparison meaningful? That depends largely on how well the warfarin group were kept within the target INR range. In the AMPLIFY trial, 5395 patients with new episodes of venous thromboembolism were randomised to apixaban twice daily for 6 months or to conventional treatment with enoxaparin followed by warfarin. The context of the trial is not described in the main paper, but from the appendix it seems to have been conducted in 28 countries, and it takes 14 pages to list the contributing centres which recruited patients. Half of them recruited fewer than ten subjects, and 31 centres recruited only one. There were numerous exclusion criteria. Overall, these hundreds of centres only managed to keep their patients within the INR target area of 2-3 for 61% of the time. So if you’re happy to accept that as your comparator, then apixaban is non-inferior to warfarin and causes fewer major bleeds. Otherwise, you might want to ask yourself why the drug companies who paid for this trial chose this way of doing it, and whether that 61% figure is what you hope for when you give warfarin to your patients.
D2B Time and Mortality Among Patients Undergoing Primary PCI (pg. 901): Over the fifteen years I’ve been watching the journals, I’ve had a grandstand view of the shift from thrombolysis to immediate percutaneous intervention as the treatment of choice for myocardial infarction. And still the shift goes on towards ever-quicker PCI, because there is good evidence that time means myocardium. This important study shows that in the USA, median door-to-balloon time in hospitals fell from 83 minutes to 67 minutes over a three year period (the years July 2005 to June 2006 compared with July 2008 to June 2009). But in-hospital mortality did not change. This is interesting but hard to interpret: much depends on what happens to the patient before reaching the hospital door. My take on all the studies—including those of thrombolysis given by paramedics—is that the sooner you reopen the coronary supply, the better. What matters critically is blockage to reopening time, not any subset of that.
Pretreatment with Prasugrel in Non–ST-Segment Elevation Acute Coronary Syndromes (pg. 999): Moving swiftly on, we get to this week’s issue of the mighty journal. Here the first paper concerns itself with a comparatively small issue in the treatment of myocardial infarction: the timing of prasugrel administration in relation to percutaneous intervention for non-ST-elevation MI. Do I see your eyes glaze over? OK, we are not all interventional cardiologists, but for the record, if you give the prasugrel before coronary catheterization, you get more bleeds but no extra benefit.
JAMA Intern Med 9 Sep 2013 Vol 173
Contraindicated Initiation of β-Blocker Therapy in Patients Hospitalized for HF (pg. 1547): I got interested in heart failure in the early 1990s, and helped to draw up the first Oxfordshire guideline on the subject. Avoid beta-blockers, we said in 1993. Then, oops, in came the first carvedilol trials, and a couple of years later we said introduce them cautiously in all stable patients without contra-indications. Now it is a matter of dogma that all patients with systolic heart failure should be on one of the beta-blockers shown to reduce mortality in a randomized trial. No choice in the matter: you must take these because you will live longer. But most patients dying from heart failure don’t want to live longer but to feel better. And in unstable heart failure, going on a beta-blocker can make you a whole lot worse. Here is a short report on the way that beta-blockers are handed out in US hospitals to heart failure patients who are at risk of clinical instability. The lead author is Kumar Dharmarajan, a brilliant young researcher who is interested in all the ways we mishandle heart failure patients when they come to hospital. He will know he has succeeded when he has nothing left to write about.
Lancet 31 Aug – 14 Sep 2013 Vol 382
Vascular and Upper GI Effects of NSAIDS (pg. 769): The disclosure of concealed harms that led to the withdrawal of Vioxx (rofecoxib) in 2004 suddenly made us aware of the cardiovascular risks of non-steroidal anti-inflammatory drugs, and from then on league tables of harm have appeared regularly. Not that they have had all that much effect. Diclofenac, which carries a risk at least as great as Vioxx, remains a highly popular drug that is still prescribed long-term to innumerable high-risk patients. Now, from the Coxib and traditional NSAID Trialists’ (CNT) Collaboration, comes what is probably the definitive examination of the relative risks of the various NSAIDs. As usual naproxen comes out best for lack of cardiovascular risk, while the others jostle for position in the harm league.
September 16th, 2013
Realistic Expectations for Renal Denervation
Larry Husten, PHD
Early trials of renal denervation have resulted in extremely impressive drops in systolic blood pressure approximating 30 mm Hg. These results have sparked a great deal of excitement in the hypertension community and stirred the interest of a multitude of medical device companies. Some experts have proclaimed renal denervation a potential “cure” for resistant hypertension, perhaps enabling a significant number of patients to eliminate all drug therapy. Other expanded uses of the technology in more moderate forms of hypertension and other diseases are under active consideration. Now, however, a new analysis of the available data suggests the troubling possibility that renal denervation may not be nearly as effective in cutting blood pressure as had been suggested in the earlier trials. Rather than reducing systolic blood pressure by 30 mm Hg, the new analysis suggests that a more realistic estimate of the effect of renal denervation may be a much more modest reduction of about 13 mm Hg.
The analysis, published online in Heart, demonstrates that the large reductions in blood pressure seen so far in clinical trials of renal denervation may be a consequence of certain key aspects in the design of these trials. The apparent blood pressure-lowering effect of renal denervation has been greatly magnified because the trials have been uncontrolled and unblinded and have utilized office-based blood pressure measurements rather than the far more reliable and consistent ambulatory blood pressure monitoring (ABPM).
When randomized and blinded trials do appear, starting next year with Medtronic’s SYMPLICITY HTN-3 Trial, “people are going to be severely disappointed,” predicts the senior author of the paper, Darrel Francis, because “the office and ambulatory effects are going to have to converge, and that will make them both in the 10-15 mmHg territory.”
Francis says that the real effect of a 10-15 mm Hg drop in pressure “is very worthwhile, but talking about 2 or 3 times that effect size does nobody any good, because it eliminates the scope for scientific discussion.”
A Medtronic spokesperson did not take issue with the conclusion that the blood pressure lowering effect of renal denervation is likely to be more modest than initially reported. “Frankly, it’s important that we set realistic expectations,” she said. The company expects that the ABPM reduction will be less than that seen with office measurements. “It’s not a cure, you’re not going to go off all your medications,” she said, in response to some of the hype that has accompanied the early trials.
“This is probably the most extreme case I have ever seen of inadvertent bias in measurement producing – concordantly across several studies – massive overestimation of an effect size,” said Francis.
Hypertension experts Franz Messerli and Sripal Bangalore agree that the hype over renal denervation is due for deflation:
Small wonder that the cookie is finally crumbling, bigger wonder that it actually took so long. The irrational exuberance for renal denervation in resistant hypertension was entirely driven by uncontrolled non-randomized observational office-based blood pressure studies. We showed that in the Spanish registry of more than 8000 patients about a quarter of patients with office blood pressures of above 160/100 were actually normotensive when monitored by 24-hour ambulatory blood pressure (ABPM). Further, in this same Spanish registry about one third of patients with resistant hypertension based on office blood pressure measurements had normotensive ABPMs. Thus many patients with so-called resistant hypertension by office blood pressure measurements may be pseudo-resistant only. This would indicate that the exaggerated benefits observed with office blood pressure measurements are due to the simple fact that some patients actually had normal blood pressure at trial baseline. Conceivably many of these patients have white coat hypertension which is unmasked by ABPM.
The lesson to be learned here is that all of these studies should either be placebo controlled or at least mandate ABPM at baseline and every follow up.
Renal denervation has not been approved for use in the U.S. by the FDA. Renal denervation products are available in Europe, and many more companies are working on new devices.
Measuring Blood Pressure
Why the discrepancy between office-based measurements and ABPM? The same discrepancy between office measurement and ABPM has also been seen in trials of blood pressure drugs, but disappears in randomized, double-blind trials. In those trials, ABPM measurements will generally be lower than office-based measurements, but the difference between the placebo and active arms will be consistent. The authors of the Heart paper offer a number of reasons why office measurements are often less reliable.
For one, in the office, physicians are likely to re-measure readings they think are inconsistent with their clinical impression of the patient. In an open study, this is especially problematic, since the physicians may be more likely to re-measure untreated patients with a low blood pressure or treated patients with a high blood pressure.
Another factor is that patients are more likely to enter a trial when they have a high blood pressure reading at the office. But in many cases this represents a higher-than-usual value for the patient, and a substantial treatment effect may then be observed by simply re-measuring the blood pressure at a later time point. This “regression to the mean” can easily lead to an overestimation of the treatment effect in an uncontrolled trial or an unblinded trial.
Another theory explaining the difference between office and ambulatory blood pressure is the “white coat effect” in which the higher blood pressures observed in the office signal a potentially dangerous “alerting response,” possibly mediated by the renal nerves. However, if this were true, then the blood pressure-lowering effect as measured by ABPM would be greater during the day, when the sympathetic nervous system is stimulated, than at night, when it is at rest. But this difference has not been observed in the renal denervation trials, according to the Heart authors.
A different but related problem is that some patients with apparent “resistant” hypertension may not actually be taking their medications as prescribed. The treatment effect in these patients may appear much greater than in adherent patients.
September 16th, 2013
Combining Randomized Trials And Registries: A New Paradigm
John S Rumsfeld, MD, PhD
Ultimately, we need clinical trials to know what drugs and medical devices work. Without them, we will not have the evidence we need for clinical practice guidelines, and clinical care will not evolve. But traditional clinical trial approaches are not sustainable – too expensive and too inefficient. The new hope for clinical trials is to use clinical registry programs to conduct them more efficiently. And that new hope is now a reality. The Swedish registry proves the concept. And the U.S. registries-– especially those in the cardiovascular area-– have also done ‘proof of concept’. The remaining barrier to this becoming the way clinical trials are conducted is to gain the collaboration-– and trust-– of industry to work with the professional society registry programs to conduct the trials. The FDA and NIH and other stakeholders support it, so I believe it will now happen. And the primary beneficiary is patients, because we can spend less to gain critical new knowledge in a shorter time.
Randomized clinical trials remain the centerpiece for scientific evidence– the evidence for what medical therapies work and should be recommended in clinical practice guidelines.
Unfortunately, traditional clinical trials are very costly and inefficient. In essence, each new clinical trial starts “from scratch,” including identifying hospitals or practices to participate, developing new case report forms, etc. And each trial includes selected patients from selected centers, who participate in the trial for a specified, usually limited, amount of time.
The expense and inefficiency of traditional clinical trials is a threat to their existence. Already we see fewer and fewer of these conducted in the U.S.
But there is a potential new paradigm for conducting clinical trials-– piggy-backing on existing clinical registries to make the trial more efficient.
The hope is that large clinical registry programs-– like those of the American College of Cardiology in the U.S. or the Swedish registry that was used for the TASTE trial published in the NEJM-– may be able to serve as a more efficient infrastructure for clinical trials.
Here is why this hope exists:
1. Large national clinical registry programs are already a network of hospitals or practices. Participants already have contracts in place to collect and combine data, for quality measurement but also for aggregated research.
2. The data elements collected in registry programs largely represent the ‘data standards’ for a given clinical area. At least 80% of the necessary data for a clinical trial is already being collected in the registries.
3. Thus, it is easy to see how a clinical registry can be used to recruit sites from the existing registry network for a clinical trial, and that only a modest amount of additional data collection may be necessary for the trial. Both of these would greatly contribute to more efficient clinical trials, from both cost and time standpoints.
4. There are other appealing aspects of this. For example:
a. Existing registry data can be used to plan clinical trials-– we know what sites provide which types of care, so a given clinical trial can use that data to target specific centers for participation (for example, for doing a certain type of procedure not done at all hospitals).
b. When a clinical trial ends, the clinical registry program will continue to document care and patient outcomes. This suggests that ‘post-trial’ surveillance can continue-– which can become ‘post-market’ surveillance for new drugs and devices. The FDA is working closely with clinical registry programs in the cardiovascular area, supporting the idea of conducting more efficient clinical trials, but then to have the registry data available for post-market safety surveillance.
Traditionally, the two worlds of clinical trials and clinical registry programs have just not overlapped, but that is no longer true. And the hope of using clinical registries to conduct clinical trials is now a reality. The Swedish registry is proof that the two can be combined to run a more efficient clinical trial. In the U.S. the American College of Cardiology’s National Cardiovascular Data Registry (NCDR) has also recently proved the concept, conducting a randomized clinical trial of angioplasty in women (called SAFE-PCI) using the registry infrastructure.
September 13th, 2013
Should We Treat Nonculprit Lesions During PCI for STEMI?
David S Wald, MA MD FRCP, Richard A. Lange, MD, MBA and L. David Hillis, MD
CardioExchange’s Rick Lange and David Hillis interview David Wald about his group’s recently published findings from the PRAMI trial of “preventive” PCI in STEMI patients.
Based on results of previous nonrandomized, observational studies, stenting non-infarct coronary stenoses during primary PCI has been discouraged. The Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial in 465 STEMI patients assessed whether performing PCI of non-infarct arteries (termed “preventive PCI”) during primary PCI (i.e., “therapeutic PCI”) would reduce the combined incidence of cardiac death, nonfatal MI, or refractory angina compared with PCI of the infarct artery only.
The PRAMI investigators report that “The use of preventive PCI to treat noninfarct coronary-artery stenoses (>50% luminal narrowing*) immediately after PCI in the infarct artery conferred a substantial advantage over not performing this additional procedure. The combined rate of cardiac death, nonfatal MI, or refractory angina was reduced by 65%, an absolute risk reduction of 14 percentage points over 23 months.” *italics indicate added phrase
Patients not included in the study were those with (a) left main disease (>50%) or left main equivalent (LAD and circumflex ostial stenoses >50%); (b) nonculprit vessel reference diameter <2.5 mm; (c) previous coronary artery bypass graft surgery; (d) chronic total occlusion as the only noninfarct stenosis; or (e) cardiogenic shock.
PRAMI has the potential to change the recommended revascularization approach in STEMI patients.
Lange and Hillis: Scrutiny of the data reveals that total deaths did not differ between the groups; 12 patients in the preventive PCI group and 16 in the therapeutic PCI group (with 2 of these before hospital discharge). Hence, the benefit of preventive PCI appears to be a reduction of subsequent nonfatal MI and refractory angina. Is this correct?
Wald: In trials such as this, all-cause mortality is an insensitive outcome measure. The results relating to the primary outcomes are the relevant measures of efficacy. An assessment of noncardiac mortality is a safety check, and the rates were similar in the two groups — which is reassuring.
Lange and Hillis: Whenever a patient has residual coronary stenoses that are not stented, the potential of treatment bias arises. The PRAMI trial is identified as being “single blind.” Who was unaware of the treatment allocated? Did the interventional cardiologist not inform the patient or the treating physician how many vessels were stented?
Wald: The patients were not aware of their assignment. It was explained to them that knowledge of the assigned treatment may bias the study, and this was accepted. The physicians were aware of the assignment.
Lange and Hillis: When PCI is compared with medical therapy, it reduces spontaneous MI at the risk of procedural MI without any difference in all MI (Bangalore et al, Circulation 2013;127:769). Because only spontaneous MIs were assessed in PRAMI, does this overestimate the benefit of preventive PCI in reducing all MIs?
Wald: It would be difficult to determine procedural MIs in this trial because all patients were having a spontaneous STEMI. The overall results would suggest that any adverse effect of procedural MI is small.
Lange and Hillis: Although the incidence of chest pain was similar in the preventive and therapeutic PCI groups (13% vs 16%, respectively), the incidence of “refractory angina” — one of the primary endpoints — was different (5% vs 13%, respectively; P=0.002). Please explain.
Wald: The former comparison (13% v 16%) relates to the extent to which ischaemia testing was used to investigate chest pain in the Preventive and No Preventive PCI groups after randomization. The latter comparison (5% v 13%) relates to refractory angina as defined in the paper.
Lange and Hillis: In the therapeutic PCI group, testing for ischemia was done more frequently in asymptomatic than in symptomatic subjects, whereas in the preventive PCI group it was done primarily in symptomatic patients. You conclude that “…these findings suggest that preventive PCI may lead to less ischemia testing and that when such testing is performed, it tends to be in patients with symptoms.” An alternative explanation is that the physicians had a bias toward revascularization, which led to more testing — and perhaps revascularization — in asymptomatic patients who did not undergo preventive PCI. How would you respond?
Wald: This is possible. To the extent that there may have been a bias towards more revascularization in the No preventive PCI group, this is likely to dilute the effect of Preventive PCI.
Lange and Hillis: Much attention has recently been focused on preventing unnecessary PCIs (i.e., in patients without symptoms or hemodynamically significant stenoses), in part related to the vagaries of visually estimating stenosis of “intermediate” severity. PRAMI has the potential of substantially increasing the use of stents in STEMI patients. How did you ensure that the PCI was not applied to <50% stenoses? Should fractional flow reserve (FFR) be measured to ensure that only hemodynamically significant lesions are stented?
Wald: Participating physicians accepted the >50% stenosis cut-off for stenting, and to the best of our knowledge, this was applied. Whether FFR in STEMI patients would be better is unknown.
September 13th, 2013
Entering New Territory with the Subcutaneous ICD
John Ryan, MD and Martin C. Burke, D.O.
Last year’s FDA approval of Boston Scientific’s subcutaneous ICD (S-ICD), the first that doesn’t use transvenous leads, was based on a pivotal trial that assessed the device’s safety and effectiveness. CardioExchange’s John Ryan asks lead investigator Martin C. Burke questions about the trial, recently published in Circulation, and the S-ICD.
Ryan: Should patients ask for the S-ICD preferentially? If it is not available at their center, what options are available for them?
Burke: Patients should be given an even presentation of data and rationale for both the single chamber transvenous ICD and the S-ICD, especially because about 3-5% of patients will fail the pre-implant ECG screening procedure and, and based on the IDE study results, another 2% will fail the acute defibrillation threshold testing part of the procedure. Thus, a small percentage of the patients eligible for the subcutaneous ICD will still require a transvenous ICD system in order to have adequate therapy to prevent sudden cardiac death.
During this pivotal subcutaneous ICD study, patients generally understood the advantages and difference in not having a wire and electrode placed in the heart and took preference with the S-ICD system. This was especially preferred by the greater than 13% of patients who were implanted after transvenous device infection and recall failure.
The S-ICD system is still only being offered at 31 implant centers in the United States and is widely available across most regions. Training new implanting electrophysiologists will take place in full swing over the next year with more centers having access by January 2014. Accessing the Boston Scientific website or talking to local Boston Scientific representatives will direct you to current centers with expertise in the screening and implantation of the S-ICD system.
Ryan: A total of 13% of study patients received inappropriate shocks. This seems high. Do you suspect that this has an effect on outcomes?
Burke: That 13% of patients received inappropriate shocks was an interesting finding in this new subcutaneous implant and sensing platform. It is certainly too much, but is comparable to pre MADIT RIT programming in the more established transvenous ICD implant platform. Differences in the mode of inappropriate shock should be clearly delineated. The S-ICD had a higher rate of inappropriate shock for T wave oversensing rather than rapid SVT, an opposite phenomenon in comparison to the transvenous ICD implant population. The classification of the rhythm was very accurate using subcutaneous sensing electrodes, while T wave amplitude was more challenging. Lessons were learned to cut the inappropriate shock rate during the study by more than 50% with reprogramming sensing vectors and rate cutoffs. Furthermore, the dataset was used to establish more stringent screening criteria for commercial implant populations, making the problem of T wave oversensing more preventable as the experience with the system becomes more wide spread. It is a goal, and attainable as signal processing exponentially becomes faster, for all ICD systems to have complete freedom from inappropriate therapy and maintain 100% appropriate therapy leading to best clinical outcome. The subcutaneous sensing science is key to successfully realize this goal.
Ryan: Patients with documented spontaneous and frequently recurring VT reliably terminated with anti-tachycardia pacing were excluded from the study — that would likely be a significant number. How many patients did this include? And how do you decide a priori if ATP compatible device is preferable for people (bearing in mind that ATP has less effect on morbidity and mortality than ICD firing)?
Burke: The exclusion criteria for the S-ICD investigational device exemption study was very narrow and did include patients with documented spontaneous and frequently recurring VT reliably terminated with anti-tachycardia pacing. There were no data prospectively collected as to how many patients were excluded for any of the pre-specified exclusion criteria. However, it should be noted that this number is generally very low in de novo patients indicated for any ICD. It is only after the implant that the majority of these patients are identified. Patients with primary and secondary prevention were included in the study cohort at similar rates to the ACC-NCDR database and this clearly indicates that patient enrollment was not overly controlled.
Finally, the subcutaneous device was not removed for any patient due to spontaneous and frequent VT reliably terminated with anti-tachycardia pacing. The interesting correlate to this fact is that 63% of VTs leading to charging of the device did not receive a shock because of the longer, more deliberate sensing algorithm delaying therapy in this S-ICD implant population. This would correlate to the Group C MADIT-RIT programming methods reported last year. Anti-tachycardia pacing remains a useful therapy modality but its need is becoming less necessary as large datasets suggest that VT is largely nonsustained and self-terminating. ICD therapy, either subcutaneous or transvenous, is predominately to reverse fibrillation and prevent sudden death. A more expansive future role of VT ablation in this population needs more study.
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