September 24th, 2013
A New Model to Predict Post-PCI Bleeding
Sunil Rao, MD
CardioExchange’s Harlan Krumholz interviews Sunil Rao about his research group’s risk model that uses an expanded definition of bleeding to predict which patients will have bleeding complications after percutaneous coronary intervention (PCI). The study is published in JACC: Cardiovascular Interventions.
THE STUDY
Investigators analyzed clinical data from the CathPCI Registry to identify factors associated with bleeding complications within 72 hours after PCI. The data set comprised more than 1 million PCI procedures performed at more than 1100 centers from February 2008 through April 2011. The definition of bleeding included several events that previous definitions have not addressed, such as intracranial hemorrhage, tamponade, reductions in hemoglobin that account for potential hemodilution, and transfusions that account for severe anemia.
Full and simplified risk scores were validated. The full model included 31 variables; the risk score had 10 variables (see Tables 3 and 4 in the published article in JACC). Under the new definition of bleeding, the overall bleeding rate was 5.8%. The full model’s discriminatory value was consistent across a variety of prespecified subgroups and across the PCI risk spectrum.
THE INTERVIEW
Krumholz: Clinicians may be feeling risk-model fatigue. What should they take away from this article?
Rao: That is a fair criticism. Many published models have examined short- and long-term mortality, acute kidney injury, and bleeding. It’s important to understand the role of these risk models in contemporary PCI practice. First, we have the simple matter of estimating a patient’s risk for an adverse event so that the conversation with the patient can be more informative. Second is the issue of risk adjustment for PCI performance measures. An outstanding article published by Dr. Krumholz in Circulation in 2000 makes clear that a performance measure should reflect a meaningful outcome to patients and society — it should be valid, reliable, easily measured, modifiable through improvements in care processes, and amenable to risk adjustments. This last element is vital. Quality-improvement initiatives should avoid penalizing sites that perform PCI on sicker patients who have a higher rate of adverse events. Risk adjustment reduces the likelihood of that unfair penalty. The model in our paper is designed to accomplish both objectives: to inform discussions with patients about the risks of PCI, and to risk-adjust bleeding outcomes as applied to the CathPCI Registry cohort.
Krumholz: If clinicians want to apply your model in practice, how do you suggest they do it? The score is not simple enough for a mental calculation (and that is not meant as a criticism).
Rao: I tend to agree. An article by Gurm and colleagues, published earlier this year in JACC, makes an argument against simple risk scores, which the authors contend do not have good discriminatory value. In the era of smartphones and electronic health records (EHRs), more-complex scores are not necessarily burdensome to calculate. I think the best way to apply these in practice is to integrate them into daily workflows. EHRs need to capture the pertinent patient variables and should be programmed to calculate the risk for relevant outcomes without requiring much physician brain power. Unfortunately, we are probably not there yet, but professional societies are in the process of developing apps that can calculate these risks at the bedside.
Krumholz: How many scores should we calculate for PCI patients?
Rao: Great question. Building on my previous answers, I think patients want to know their risk for any adverse event, a portion of which we cannot quantify because some events are rare and may depend on unknown factors. That said, we can calculate some of the major risks such as bleeding, acute kidney injury, and mortality. In an ideal world, our EHR would calculate these automatically for a patient who is scheduled for catheterization and PCI.
Krumholz: Are you using these risk models in your practice?
Rao: We can certainly do better. We use them in cases that are deemed to be “complex,” but doing it routinely is the way to integrate it into practice. Like the physical examination, it should become part of the patient evaluation. Again, the role of the EHR is paramount. If robust models generate the risk for adverse events electronically, we can have a more informed conversation with the patient, which will then become part of our practice. We should aim to get to the point where not quantifying a patient’s risk is rare.
JOIN THE DISCUSSION
Are you ready for a new risk model for post-PCI bleeding? What do you consider the strengths and limitations of the model from Dr. Rao’s study group?
September 23rd, 2013
Using Registry Data, FDA Expands Indication for Edwards’ Sapien Transcatheter Heart Valves
Larry Husten, PHD
Relying on an important new source of information, the FDA said today that it had expanded the label for the Sapien Transcatheter Heart Valve (Edwards Lifesciences). Previously, the Sapien was approved for insertion via the transfemoral or transapical access points in patients not eligible for traditional aortic valve surgery. The new labeling no longer mentions access points and therefore allows for alternative access points such as the subclavian.
The most significant part of the FDA’s announcement may be not the label change itself but the source of the data supporting the claim — the Transcatheter Valve Therapy Registry (TVTR). The TVTR, which is run by the American College of Cardiology and the Society of Thoracic Surgeons, has emerged as an model of cooperation between the FDA, industry, and medical organizations. The TVTR data, according to the FDA, show no evidence that the access point changed the benefit-risk profile or the device.
“Just two years after the THV entered the market for a specific patient population, data from the TVTR was used to support FDA approval that expands patient access to a life-saving therapy,” said Jeffrey Shuren, the director of the FDA’s Center for Devices and Radiological Health, in an FDA press release. “Medical device registries like the TVTR not only play an important role in the FDA’s post market surveillance system, they also collect robust and timely data that can be used to identify additional patient populations that benefit from the therapy. “
“Leveraging clinical research inside the framework of a device registry to expand access to therapy for more patients is a new paradigm for the FDA, researchers, registry sponsors and the medical device industry,” said Shuren. “We believe this approach can be used with future well-designed device registries to speed patient access to important, well-evaluated therapies.”
September 23rd, 2013
HDL-P: The Better Marker of Residual Risk?
Samia Mora, MD, MHS
In a new analysis of data from the JUPITER trial, researchers found that high-density lipoprotein particles (HDL-P) may be a better marker of residual risk than chemically measured high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-1 (apoA-1). CardioExchange’s editor-in-chief Harlan Krumholz interviewed lead investigator Samia Mora about the analysis, which was recently published in Circulation.
Harlan Krumholz: You previously showed in the JUPITER trial that on-treatment HDL-C was not predictive of residual risk among statin-treated individuals, while HDL-C was predictive among those taking placebo. Should we have risk-stratification tools that are specific to whether patients are taking statins?
Mora: It is not yet clear whether specific risk-stratification tools should be used for patients taking statins compared with those not taking statins, and whether such a strategy would improve outcomes among statin-treated patients. What is clear is that vascular events among statin-treated patients remain common, especially among patients with known vascular disease, and that there may be other risk factors or determinants of residual risk among statin-treated patients. For example, in the TNT trial of patients with known coronary disease, standard risk factors and other known clinical variables explained a moderate amount of the residual risk. However, the c-index of 0.7 suggested that additional factors may contribute to residual risk.
Our earlier JUPITER results provocatively suggested that on-statin HDL-C levels were not associated with residual vascular risk, but we were unable to rule out a possible association for HDL-C with residual risk in JUPITER because of the relatively small number of events in the rosuvastatin arm. In a recent meta-analysis of eight statin trials (including JUPITER) among 38,153 statin-allocated patients with a total of 5387 vascular events, on-treatment HDL-C levels were predictive of residual risk.
Harlan Krumholz: In your new article you suggest that other indices of HDL might be more useful in patients on statins. How did you come up with that hypothesis?
Mora: Our hypothesis was driven by our earlier intriguing findings from the MESA study. Among statin-naïve individuals, the number of HDL-P was a better predictor of subclinical atherosclerosis and clinical events compared with HDL-C.
Harlan Krumholz: You find that HDL-P is predictive in patients on rosuvastatin but not in those on placebo. Given this finding, what should practicing doctors do now?
Mora: In our current study from JUPITER, we found that the number of HDL-P was associated with incident vascular events among both the placebo- and rosuvastatin-allocated groups, and was a better predictor of residual risk among the rosuvastatin-allocated group than HDL-C or apoA-1. Our results should be viewed as hypothesis generating and will require further evaluation in other studies before they can be applied clinically. However, the current results from JUPITER along with the earlier results from MESA highlight that HDL-C is not the same measure as HDL-P number, and that other properties of HDL may be significant. We just don’t know what we should do about them. Practicing doctors can reduce residual risk by applying and reinforcing multi-factorial risk reduction strategies that have been demonstrated to be efficacious and life-saving.
Harlan Krumholz: Also, if you are a patient on statins, can you now ignore your HDL level?
Mora: HDL levels can be measured with various tests, such as HDL-C, HDL-P number, HDL size, HDL function, apoA-1, and many other emerging properties of HDL. Our current study suggests that patients with a low HDL-P number on statin therapy are more likely to suffer from vascular events compared with individuals who have a low HDL-Con statin therapy. We just don’t know yet what is the best way to reduce this “HDL-related” risk.
Harlan Krumholz: We have seen patients whose HDL levels declined on statins, do you have any evidence about what that does to risk?
Mora: The best observational evidence to-date addressing this question comes from the large meta-analysis of 38,153 patients, which had enough events by strata of HDL-C change. In that study conducted among statin-allocated patients, neither an increase nor a decrease in HDL-C levels related to subsequent vascular risk. By contrast, an increase in apoA-1after statin allocation was associated with a reduction in subsequent vascular events. Interestingly, apoA-1 is more correlated with HDL-P than it is with HDL-C, but we don’t have enough data to address whether an increase in HDL-P number after statin therapy would result in better outcomes.
September 23rd, 2013
Selections from Richard Lehman’s Literature Review: September 23rd
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 19 Sep 2013 Vol 369
Randomized Trial of Preventive Angioplasty in MI (pg. 1115): Interventional cardiologists are gun dogs. A cardiologist who spots a stenosis wants to rush off and do something, like a springer spaniel hearing the rustle of a pheasant in the covert. Following the COURAGE study, we are trying to retrain our cardiology springers to ignore stable angina on optimal medical treatment: “No, Doc! Sit! Stay!” we tell them, as they quiver and make whimpering noises. But the PRAMI study will let them off the leash to stent at their hearts’ content when faced with acute myocardial infarction. Patients with ST elevation MI in five large British hospitals were randomised to receive immediate percutaneous intervention for the “culprit lesion” alone, or for as many significant stenoses as the cardiologist felt worth stenting. The trial was stopped early when it was clear that there was a big benefit from the latter approach: “Hazard ratios …were 0.34 (95% CI, 0.11 to 1.08) for death from cardiac causes, 0.32 (95% CI, 0.13 to 0.75) for nonfatal myocardial infarction, and 0.35 (95% CI, 0.18 to 0.69) for refractory angina” during a mean follow-up of 23 months. Woof!
JAMA 18 Sep 2013 Vol 310
Effect of Aliskiren on Progression of Coronary Disease in Patients With Prehypertension (pg. 1135): The AQUARIUS trial is just the latest in which Novartis fails to find a market for aliskiren, a renin blocker which was first licensed six years ago. They hoped to use it in people with “pre-hypertension” and coronary disease, and used a surrogate outcome: coronary atheroma measured by intravascular ultrasound. I can’t do better than to quote a tweet from Ken Covinsky: Rx of pre-htn (not a disease) wth aliskiren doesnt reduce atheroma volume (not an outcome) That was helpful. Not.
Anticoagulation With Otamixaban and Ischemic Events in NSTE-ACS (pg. 1145): At the moment my bedtime reading is Peter Gøtzsche’s damning indictment of the drug industry, Deadly Medicines and Organised Crime, which has just been published by Radcliffe. It’s a must-read. He describes all the ways that companies running trials manipulate the results or hide them altogether. But this week I am going to praise three industry run trials for their integrity, because they all show the opposite of what the manufacturer was hoping for. The first is the AQUARIUS trial described above, run by Steve Nissen, with company sponsorship, but without company control of the data; and the third is the HERA trial in The Lancet. In the middle lies this trial of otamixaban. It sounds like a treatment for otitis externa, but otamixaban is actually the latest direct factor X inhibitor to reach a crowded market. The TAO trial was designed by its manufacturer to “compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy.” But sadly for Sanofi, “Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding.” So onwards to another trial for some other indication—though it’s a fair bet it won’t involve a direct comparison with another drug in the same class.
September 22nd, 2013
Join a Conversation About Health Care Innovation
CardioExchange Editors, Staff
The New England Journal of Medicine and Harvard Business Review have teamed up to launch a series on Leading Health Care Innovation. Among the features is a one-hour webinar this Tuesday, September 24, led by Michael E. Porter, of Harvard Business School, and Thomas H. Lee, MD, the chief medical officer at Press Ganey and the former network president of Partners HealthCare. They will discuss their brand-new article “The Strategy That Will Fix Health Care.”
We encourage you to read the content at the HBR-NEJM Insight Center, to join the webinar if you are able, and to report back here with your thoughts about the implications of these ideas for the field of cardiology and for the health care system more broadly. Here are the relevant links:
HBR-NEJM Insight Center on Leading Health Care Innovation
Free registration for the Sep 24 webinar
“The Strategy That Will Fix Health Care,” by Michael E. Porter and Thomas H. Lee
September 20th, 2013
Taking a Clear-Eyed View of Statins and Cataracts
Larry Husten, PHD
Past observational studies have turned up conflicting findings about the effects, if any, of statins on developing cataracts. Now a large new observational study finds a small but significant increase in cataracts in statin users, however, experts warn that without further support the new finding should probably not influence clinical practice.
In a paper published in JAMA Ophthalmology, Jessica Leuschen and colleagues analyzed data from a military health care system. In their primary analysis they performed a propensity analysis comparing 6,972 propensity-matched pairs of statin users and nonusers. The authors reported a significant 9% increased risk among statin users compared with nonusers (odds ratio 1.09, CI 1.02-1.17). Secondary analyses, and a sensitivity analysis based on duration of statin treatment, appeared to confirm the association. The authors said that their study was less likely to reflect bias from health care accessibility and use because of the military setting.
The authors concluded:
The risk for cataract is increased among statin users as compared with nonusers. The risk-benefit ratio of statin use, specifically for primary prevention, should be carefully weighed, and further studies are warranted.”
However, in a comment for NEJM Journal Watch, JoAnne Foody said:
“Data on whether statins increase risk for cataracts remain inconclusive and conflicting. For now clinicians should continue to weigh individual patient … benefits and potential harms in determining whether statins are the right choice for a given patient.”
Another statin expert who wishes to remain anonymous said that even if cataract risk was increased by a small amount, the substantial benefits of statin therapy would continue to outweigh the risks, especially since treatment for cataracts is extremely safe and effective.
September 20th, 2013
My Stent Is Better Than Your Stent
Richard A. Lange, MD, MBA and L. David Hillis, MD
In a meta-analysis of the final 3-year results of the international SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) II, III, and IV clinical trials, coronary implantation of the everolimus-eluting stent (EES) was superior to the use of the paclitaxel-eluting stent (PES), with reduced rates of all-cause death, myocardial infarction (MI), ischemia-driven target-lesion revascularization (TLR), stent thrombosis, and target-lesion failure (a composite of cardiac death, target-vessel MI, and ischemia-driven TLR).
EES (%)(n=3350) |
PES (%)(n=1639) |
Hazard ratio |
P value |
|
Mortality |
3.2 |
5.1 |
0.65 |
0.003 |
MI |
3.2 |
5.1 |
0.64 |
0.002 |
Ischemia-driven TLR |
6.0 |
8.2 |
0.72 |
0.004 |
Stent thrombosis |
0.7 |
1.7 |
0.45 |
0.003 |
Target-lesion failure |
8.9 |
12.5 |
0.71 |
0.0002 |
1. With all the different stents available, how do you decide which stent(s) to use?
2. What factors affect your decision (i.e., product, patient, personal, cath lab stock, etc) ?
3. To what extent is your choice evidence-based? If 0% is personal opinion and 100% is entirely data-driven, how “evidence-based” is your choice?
4. Each stent manufacturer extols the virtues of its own product. Where do you get your information regarding stent superiority?
September 19th, 2013
Clopidogrel’s Benefits Seen Mainly in Smokers
Nicholas Downing, MD
Clopidogrel appears to offer more protection against cardiovascular events among smokers than nonsmokers, according to a systematic review in BMJ.
Researchers examined data from six randomized trials comparing clopidogrel (alone or with aspirin) with control treatments (namely, aspirin alone or lower-dose clopidogrel plus aspirin). Nearly 75,000 patients with established cardiovascular disease, 30% of whom were smokers, were included.
Among smokers, clopidogrel was associated with a 25% reduction in the composite outcome of cardiovascular death, MI, or stroke; however, among nonsmokers, it conferred only an 8% reduction. (In a separate analysis, they also found that prasugrel or ticagrelor “seemed to be more efficacious” than clopidogrel in smokers and “marginally more efficacious” in nonsmokers.)
The researchers conclude: “Different risk-benefit considerations might be required for smokers and nonsmokers.”
September 19th, 2013
A Novel Navigation System for CRT Device Implantation
Sergio Richter, MD
CardioExchange’s editor-in-chief Harlan Krumholz interviews Sergio Richter, lead investigator of a new study of a non–fluoroscopy-based tracking system that can be used when implanting a cardiac resynchronization therapy (CRT) device. The study is published in Circulation: Arrhythmia and Electrophysiology
THE STUDY
Investigators used a novel, sensor-based electromagnetic tracking system (MediGuide) for implanting a CRT device in 15 consecutive patients who had an established indication for CRT. The system was successfully implanted with a lateral or posterolateral LV lead position in all patients. The mean total procedure time was 116 minutes, the median total fluoroscopy time was 5.2 minutes, and the median fluoroscopy time for LV lead deployment was 2.6 minutes. There were no severe complications that required an acute intervention or reoperation during the peri- or postoperative periods (patients were followed for 4 weeks after implantation). The system’s manufacturer funded the study.
THE INTERVIEW
Harlan Krumholz: Non–fluoroscopy-based technology has been used for catheter ablation and coronary interventions. Please explain how it works and whether it has features that are unique to the CRT system.
Richter: Conventional fluoroscopy is still needed for transvenous implantation of cardiac pacing devices, but the MediGuide system has the potential to substantially reduce the radiation time and exposure. Implantation of the right atrial and right ventricular leads requires conventional fluoroscopy. Thereafter, recording of cineloops in different angulations is necessary. Intubation of the coronary sinus is possible with a sensor-equipped outer sheath and EP catheter without use of radiation (in the vast majority of patients). The occlusive venography of the coronary sinus again requires radiation, but from then on it’s possible to work on these ECG-gated cineloops. The tip of different LV-lead delivery tools (outer sheath, inner sheath for subselection of side branches, and guidewires) is non-fluoroscopically displayed within the system. The CRT device is a conventional one, and the final positioning of the LV lead again requires fluoroscopy, as the lead itself is not equipped with a sensor.
Harlan Krumholz: The mean fluoroscopy time for CRT procedures is 22 minutes, compared with a median fluoroscopy time of 5 minutes in your study. What should a health system be willing to pay to avoid 17 minutes of fluoroscopy?
Richter: The biggest benefit of reducing fluoroscopy time and exposure is on the implanting physician’s (not the patient’s) side, as the patient receives the radiation exposure only once, not daily. The cost ought to be absorbed by the physician’s employer, which should seek maximum safety for its employees who conduct these procedures routinely.
Harlan Krumholz: How difficult is it to learn this system?
Richter: The system is very easy to learn. Different tools for delivery of the LV lead are equipped with an electromagnetic sensor at the tip. They have to be cable-connected to the patient’s interface unit of the MediGuide system. The handling differs nonessentially from the original tools, and the operation time is only slightly prolonged. During the very first implantations using the new system, we had to adjust to the fact that only the tip is displaced on the screen and one cannot “see” the behavior of the shaft of the used tools. But after a steep learning curve, it became easy to work with the system.
Harlan Krumholz: What are the next steps in evaluating the system?
Richter: Our institution is preparing a case-control study with nearly 60 patients implanted with the new electromagnetic tracking system. A prospective randomized trial comparing CRT device implantation with the MediGuide system versus conventional fluoroscopy is underway.
Harlan Krumholz: What do you predict about the use of these systems in the future?
Richter: Electromagnetic navigation has the potential to gain a better spatial anatomical orientation and reduce radiation exposure during invasive cardiovascular interventions.
Moreover, the capability of real-time sensor tracking offers the possibility to record or map actual wall-motion data from the endocardium and epicardium of the left ventricle. Such information may become relevant for tailored LV lead positioning, to optimize CRT response and clinical outcome in patients with congestive heart failure. It’s also possible to envision an extended use of this technology during complex coronary interventions, implantation of transfemoral valves, or interventions at the great arteries.
Harlan Krumholz: What is your response to people who express concern that the authors have received honoraria from the manufacturer of this product?
Richter: All authors received lecture honoraria and conference sponsorship from different companies. This has nothing to do with the design and development of the system or the integration into our clinical workflow. St. Jude Medical, the manufacturer of the system, funded the study, but none of the authors received honoraria directly associated with this particular study.
JOIN THE DISCUSSION
How much promise do you think the MediGuide system holds for the future of CRT device implantation?
September 18th, 2013
Disparities in Rate of Inappropriate Use of PCI
Paul S. Chan, MD, MS
CardioExchange’s editor-in-chief Harlan Krumholz asks Paul Chan some questions about his new study in JACC that found a surprising pattern of both overuse and underuse of PCI among different populations in the U.S. For a summary of the findings, see CardioExchange’s news coverage of the paper.
Harlan Krumholz: The paper would be consistent with a hypothesis that patients for whom physicians are paid more are more likely to undergo inappropriate procedures? Is that true?
Paul Chan: Our findings by insurance status would seem to suggest this. We found a gradation by insurance status in the likelihood of undergoing an elective PCI categorized as inappropriate (i.e., with a low likelihood of clinical benefit). Whereas publicly insured patients were only 15% to 20% less likely to undergo an inappropriate PCI compared with privately insured patients, uninsured patients were half as likely. It is not clear, though, whether this was mediated at the physician level, or, more likely, at the hospitals at which predominantly uninsured and publicly insured patients received care.
Harlan Krumholz: Do you think that the lower rate of procedures in non-white populations might be due to overuse in white populations?
Paul Chan: There are 2 types of potential disparities in care. I do not think that a racial difference in a “hard” clinical end point would be disputable. For instance, we have previously found that non-whites have a substantially lower rate of survival compared with whites for cardiac arrests within hospitals, and I doubt anyone would dispute that this difference is unacceptable. Where there is some uncertainty is when there is a racial difference in a treatment or an intervention. There are numerous studies which have documented underuse in a treatment in non-white populations. What our study intimates is that some of the racial differences in treatment may also be due to potential overuse. Therefore, efforts to end racial disparities may be more complex– eradicating underuse among vulnerable populations in circumstances where there is clear clinical benefit of treatment for patients, but also addressing potential overuse which may contribute to the measured racial differences.
Harlan Krumholz: Why would white men be more likely to have inappropriate procedures?
Paul Chan: We found this to be a head-scratcher, too. Unlike differences by race and insurance status, I would imagine the representation of women across Cath PCI sites was pretty homogeneous, so this difference would be unlikely to be mediated by the hospital at which men and women received care. If anything, since women are more likely to present with atypical symptoms which could be coded as having no or minimal symptoms, I would not have been surprised were women found to have higher rates of PCIs categorized as inappropriate. It could be that women’s propensity to have more common presentations of diffuse coronary artery disease may have led to less aggressive treatment in clinical settings where symptoms, angiographic findings, and stress test results were not high-risk (i.e., less frequent PCIs for inappropriate indications).
Harlan Krumholz: What are the implications of these findings for clinicians and policymakers?
Paul Chan: We have come a long way in ensuring that care is delivered equitably and thoughtfully in the U.S., and there is no doubt that underuse in certain populations remains a persistent and huge problem. For policymakers, as mentioned in my response to the second question, 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.
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