The new cholesterol guideline: is it really a paradigm shift?

There's a lot of misinformation flying around about the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Some of the popular distortions include the idea that the guideline authors threw away the LDL targets and sent a message that lipid lowering doesn't matter. That's not what the document says at all. Over and over in the guideline the authors acknowledge that cholesterol reduction is the goal of statin therapy. Heck the title of the guideline, as linked above, makes that pretty explicit! And while they de-emphasized specific targets they didn't throw them out altogether. What the panel did was recognize that major lipid lowering trials were not designed to test titrated dosing of drugs to particular targets. Accordingly the major recommendations of the document are based on patients' overall risk more than their lab values. In the nine years since the ATP update on lipid management we've learned a great deal about the pleiotropic effect of statins. But LDL reduction remains an important part of the story and the guideline writers acknowledge that. There's no new paradigm here. They are merely making the recommendations more respectful of historic clinical trial design. I think it's a mistake to extend the interpretation beyond that.

Last month Dr. Robert Centor, blogging ad DB's Medical Rants, expressed his approval of the new guidelines. I agree with him that we needed a more evidence based approach. But then DB makes this statement:

The brilliance of the new guidelines comes from the writing group understanding that lowering the cholesterol level does not improve important outcomes, but statins (discovered and popularized because they lower cholesterol) improve outcomes regardless of ones initial cholesterol. Other drugs that lower cholesterol or raise HDL do not improve important outcomes!

But wait a minute. There's a substantial body of research showing that lipid lowering reduces clinical events no matter how you do it. Though some of the studies have confounders, as a whole they point to the importance of LDL reduction. The Oslo study, though confounded by more smoking cessation in the intervention group, suggested a reduction in coronary events attributable to dietary reduction of cholesterol. The LRC trial showed a reduction in events attributable to LDL lowering by means of cholestyramine resin. Clinical trials of other non statin drugs also showed reduction events attributable to lipid lowering though confounded by the ability of those particular drugs to raise HDL cholesterol: the Coronary Drug Project (niacin), the WHO study (clofibrate); and the Helsinki study (gemfibrozil).

Sidebar: the Coronary Drug Project also serves as a reminder that we had comparative effectiveness research back in the 1960s. The concept is not new, only the name designed to serve political ends and give authors catchy options for their titles.

The importance of LDL in the pathogenesis of atherosclerosis has been established for a long time. Our understanding of how that works is more nuanced than it was decades ago. In our more complex understanding of atherosclerosis and new appreciation of the pleiotropic effects of statin drugs we realize more than before that the LDL concentration is not the whole story. But it remains an important part of the story.

Background: This review, though out of date for treatment recommendations, is a careful analysis of early trials establishing the lipid hypothesis and demonstrating improvement in meaningful clinical outcomes with diet and non statin drug treatments to lower cholesterol.

Extracorporeal life support (ECLS)

This refers to either extracorporeal membrane oxygenation (ECMO) or extracorporeal CO2 removal (ECCO2R), for a variety of indications but mainly ARDS. Here is a recent review.

The status of ECLS is evolving. In the 70s, following an early wave of enthusiasm for ECMO as treatment for ARDS, research evidence was disappointing. By the time of my early interest in critical care the idea was almost rejected out of hand. Subsequently it began to emerge as a rescue modality for ARDS in cases of therapeutic desperation. Technology improved and offered variations of the technique as additional options. Out of necessity considerable positive experience was gained during the 2009 pandemic. Also, as quoted from the review:

Also that same year, the conventional ventilatory support versus ECMO for severe adult respiratory failure (CESAR) study was published. The investigators used a “pragmatic” study design and were criticized for the inability to standardize mechanical ventilation management in the conventional care group.[30] Importantly, the CESAR trial demonstrated that protocolized care that included ECMO in an expert center for ARDS care yielded higher survival than the best standard care in tertiary intensive care units in the UK.[30]

Here is the CESAR study. It concluded:

We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability.

So ECLS is making its way into clinical practice. The Extracorporeal Life Support Organization has published guidelines. The indications section reads:

A.

Indications

Acute severe heart or lung failure with high mortality risk despite optimal conventional therapy. ECLS is considered at 50% mortality risk, ECLS is indicated in most circumstances at 80% mortality risk. Severity of illness and mortality risk is measured as precisely as possible using measurements for the appropriate age group and organ failure. See patient- specific protocols for details. 

B.

Contraindications

Most contraindications are relative, balancing the risks of the procedure (including the risk of using valuable resources which could be used for others) vs. the potential benefits. The relative contraindications are: 1) conditions incompatible with normal life if the patient recovers; 2) preexisting conditions which affect the quality of life (CNS status, end stage malignancy, risk of systemic bleeding with anticoagulation); 3) age and size of patient; 4) futility: patients who are too sick, have been on conventional therapy too long, or have a fatal diagnosis. See patient-specific protocols for details.

Adipose tissue: metabolically active, proinflammatory

This review from the Archives of Medical Science helps explain the cardiovascular consequences of the metabolic syndrome.

Strengthened FDA warnings for Lexiscan and Adenoscan

New from the FDA:

The U.S. Food and Drug Administration (FDA) is warning health care professionals of the rare but serious risk of heart attack and death with use of the cardiac nuclear stress test agents Lexiscan (regadenoson) and Adenoscan (adenosine). We have approved changes to the drug labels to reflect these serious events and updated our recommendations for use of these agents. Health care professionals should avoid using these drugs in patients with signs or symptoms of unstable angina or cardiovascular instability, as these patients may be at greater risk for serious cardiovascular adverse reactions.

This was already reflected in the labeling but the warning has been strengthened. The risk is believed to be low, though the denominator is unknown. The last sentence in the quoted text is of concern, given a general perception that these agents should be safer in potentially unstable patients as opposed to dobutamine or treadmill exercise.

Therapeutic hypothermia after cardiac arrest: what’s optimum?

Results of two trials were presented at AHA.

In this one 33 C was no better as a therapeutic target than 36 C in terms of survival or neurologic outcome.

In the other study initiation of cooling pre-hospital was associated with greater incidence or re-arrest and need for diuretics but produced no survival or neurologic benefit.

Based on a related discussion at Medpage Today therapeutic hypothermia remains an important intervention. However we have yet to find the sweet spot in terms of optimal timing and “dose” of the intervention.

Immediate blood pressure lowering in ischemic stroke

In patients with acute ischemic stroke not receiving thrombolytics, the guidelines for years recommend avoidance of antihypertensive therapy up to levels of 220/120 (permissive hypertension). High level evidence to guide clinicians in one direction or the other, however, was lacking. The recently published CATIS trial (presented at AHA and published in JAMA) addressed the question:

Objective To evaluate whether immediate blood pressure reduction in patients with acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge.

Design, Setting, and Participants The China Antihypertensive Trial in Acute Ischemic Stroke, a single-blind, blinded end-points randomized clinical trial, conducted among 4071 patients with nonthrombolysed ischemic stroke within 48 hours of onset and elevated systolic blood pressure. Patients were recruited from 26 hospitals across China between August 2009 and May 2013.

Interventions Patients (n = 2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 hours after randomization, achieving blood pressure less than 140/90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discontinue all antihypertensive medications (control) during hospitalization (n = 2033)…

Results Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (−12.7%) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (−7.2%) in the control group within 24 hours after randomization (difference, −5.5% [95% CI, −4.9 to −6.1%]; absolute difference, −9.1 mm Hg [95% CI, −10.2 to −8.1]; P less than  .001). Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization (difference, −9.3 mm Hg [95% CI, −10.1 to −8.4]; P less than  .001). The primary outcome did not differ between treatment groups (683 events [antihypertensive treatment] vs 681 events [control]; odds ratio, 1.00 [95% CI, 0.88 to 1.14]; P = .98) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups (500 events [antihypertensive treatment] vs 502 events [control]; odds ratio, 0.99 [95% CI, 0.86 to 1.15]; P = .93).

Conclusion and Relevance Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge.

There are no findings from this new trial to indicate change from current guideline based practice.

Another novel anticoagulant scores against warfarin

ENGAGE AF was presented at AHA and published in NEJM:

Methods

We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding…

Conclusions

Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes.

The interpretation of the results is complex. Here is a related discussion in Medpage Today.

Pitfalls in the evaluation of patients for B12 deficiency

From a recent study:

Methods This retrospective study reviewed the electronic medical records of 192 patients initiated on intramuscular vitamin B12 injections.

Results Only 12 patients had objectively documented hematologic responses: decrease of mean corpuscular volume by greater than or equal to 5 fL with stable or improved hemoglobin. Another 5 patients had equivocal hematologic responses. There was one plausible neurologic response. Thus, only 18 (9.4%) of 192 patients had data supportive of a clinical response. In these 18 patients, the baseline serum B12 level was less than or equal to 107 pg/mL; only 3 patients also had a baseline serum methylmalonic acid level, which was greater than or equal to 1.29 μmol/L in all 3 patients.

Conclusions Currently, only a small minority of patients initiated on intramuscular vitamin B12 supplementation derive any meaningful clinical benefit. Furthermore, current testing recommendations for vitamin B12 deficiency are usually not followed.

The authors make several suggestions to improve diagnostic accuracy:

Reserve B12 testing for patients with a clear clinical indication.

Avoid reliance on a single test.

Laboratories should perform reflex testing of MMA levels and IF antibodies when low B12 levels are detected.

Hematologic responses should be followed during treatment and if the expected response does not occur evaluation for other conditions should be carried out.

Biochemistry free and easy

A free on line text form OSU.

Financial struggles for hospitals

---will continue in 2014 according to a recent Moody's Investors Service report. The report was linked by Danielle Scheurer over at The Hospitalist Leader. She wrote:

Moody’s Investors Service predicts the financial outlook for US not-for-profit hospitals will be no better in 2014 (and which has been negative since 2008). They expect hospitals will continue to see tight margins, as revenue will not keep up with expenses..

Overall, for hospitalists, this will have to translate into a continued and fierce focus on Value (Quality / Cost) for all of us, to maintain feasible operating margins within our hospitals..

Of course this goes back beyond 2008. Hospitals have struggled for decades and it just steadily gets worse. The biggest tsunami for hospitals happened in 1984 with the advent of DRGs. It's just been a gradual continuum of more and more intrusive regulation and financial challenges ever since. Obamacare, whatever ultimately becomes of it, will likely just be another phase of that continuum. It will be disruptive but probably not as disruptive as what we saw in 1984.

But people lose pieces of their memory. I recall sitting in a large conference room in 1983 or 84. The speaker, talking about the advent of DRGs, warned the audience: “Doctors, you are about to be held accountable for providing high quality health care efficiently and at a low cost.”

Fast forward to 1994. Despite the demise of the Clinton health care plan managed care had already adopted the model and was poised to advance like a steamroller. And there was another conference room, another speaker who said: “Doctors, you are about to be held accountable for providing high quality health care efficiently and at a low cost.”

Fast forward to about a month ago in a conference room at the Hyatt, at UCSF's hospital medicine course. Bob Wachter, course director, stood up and spoke those same words. As if it was something new.

Reports like this remind me to try and be a better steward of medical resources. The unfortunate consequence for hospitalists has been the redefinition of core skills from clinical to business.

Electronic medical records

For a number of years now electronic medical records (EMRs) have been promoted by politicians and policy experts who know little about clinical medicine on the ground. Alongside this have appeared publications which purport to show beneficial clinical effects of EMRs. Virtually all of those, however, have reported low level and unvalidated surrogates for quality. The evidence that's out there does not convince that EMRs improve meaningful clinical outcomes. Dr. Robert Centor, the blogger at DB's Medical Rants, recently wrote a post about the unfulfilled promise of EMRs. Much of what he said concerned how they undermine diagnostic accuracy, a point with which I heartily agree and plan to elaborate on in a future post. But he concluded with this:

EHRs could help medical care. Currently it is only making physicians more busy work.

Much of the busy work he was referring to comes from what is known as computerized physician order entry (CPOE). CPOE was touted for various reasons as a process for enhancing patient safety and reducing errors. Again there was only soft and flawed surrogate evidence in support of that claim. But the main thing to understand about CPOE is that it is nothing more than shifting the workload of order processing from the traditional ward secretary to the physician. Unlike the ward clerks, though, doctors lack secretarial skills. Sure the reduction in secretaries saves hospitals money. But whether it improves patient safety by taking a link out of the chain of process or jeopardizes patients by removing a layer of safety (the secretary, usually more skilled in the processing and administrative aspects of implementing orders) is unknown.

Computerization of medicine is great in the abstract. Superficially it's a can't miss idea. That's why people in leadership who are removed from direct patient care can't understand our hesitation and our many objections. The unintended consequences are huge and difficult to navigate. Someday we will learn to use the EMR for all it is worth. Only then can we be confident that patients are better off as a result. It may take another decade.

The TACT diabetes substudy: How far can the apple fall from the tree?

The other day in the doctors lounge a colleague asked me if I had heard about a new study presented at AHA showing a benefit of chelation therapy in diabetics. I'm not big on sound bite medicine and often don't get around to reading, let alone blogging about such things for a month or more. So I told him no I hadn't, but it had better be an improvement over the recent TACT study, which I thought was seriously flawed.

I found it Saturday over morning coffee. And no, it was not an improvement over TACT. It was merely a subgroup analysis of TACT itself. Most of you have heard the buzz by now so I'll cut straight to the study, which was simultaneously published in one of the Circulation journals. Here's the link. From the paper:

Methods and Results—Patients received 40 infusions of EDTA chelation or placebo. A total of 633 (37%) patients had diabetes mellitus (322 EDTA and 311 placebo). EDTA reduced the primary end point (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina; 25% versus 38%; hazard ratio, 0.59; 95% confidence interval [CI], 0.44–0.79; P less than 0.001) for over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI, 0.39–0.88; adjusted P=0.002). All-cause mortality was reduced by EDTA chelation (10% versus 16%; hazard ratio, 0.57; 95% CI, 0.36–0.88; P=0.011), as was the secondary end point (cardiovascular death, reinfarction, or stroke; 11% versus 17%; hazard ratio, 0.60; 95% CI, 0.39–0.91; P=0.017). However, after adjusting for multiple subgroups, those results were no longer significant. The number needed to treat to reduce 1 primary end point over 5 years was 6.5 (95% CI, 4.4–12.7). There was no reduction in events in non–diabetes mellitus (n=1075; P=0.877), resulting in a treatment by diabetes mellitus interaction (P=0.004).

Conclusions—Post–myocardial infarction patients with diabetes mellitus aged greater than or equal to 50 demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. However, they do not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes mellitus.

The hype surrounding this paper will be misleading. Before I get to that, some other links of interest. Here is a discussion piece from the Heart.org, now part of Medscape Cardiology (free full text after registration). The piece is less than appropriately critical of the study but does provide some details for those without full text access to the original paper. Also found at the Medscape site is this article by Dr. John Mandrola (who blogs at Dr. John M). I think Dr. John is way too kind to the study and his tone, as reflected in the title Chelation Therapy: Promising for Diabetic Patients but Disruptive to the Medical Establishment is a little incendiary. From his introductory comments:

Based on this analysis of TACT, only six patients with diabetes had to be treated with chelation to prevent one adverse outcome. That's less than half the NNT when statins are used in patients with diabetes and established vascular disease—an uncontroversial indication.

Yet the medical establishment is overcome with doubt.

What does he mean by the medical establishment? If he means an organized body of leaders in medicine who stand for good ethics and scientific integrity, put me in that camp. That medical establishment has good reason to be upset about TACT. But perhaps Dr. John means something different. He says:

One of the doctors whom I hold in highest regard sent this to me in relation to the establishment:

The machine depends on people being sick to function. If people take control of their own health, the machine falls apart. And it is a billion-dollar business. Who wouldn't aggressively denounce anything that threatens it?

The disruption wrought by the new cholesterol guidelines pales in comparison to the angst surrounding chelation therapy.

Dr. John is talking around a very serious accusation: that professionals in mainstream medicine don't want patients to get well and stay well by taking charge of their own health. It's a somewhat conspiratorial idea but popular enough. The suggestion is that doctors in conventional medicine don't want their patients to be empowered. Is that what he really meant?

How should we interpret the study? First the usual objections. Be cautious about basing treatment recommendations on just one trial. PROWESS and many other studies taught us that lesson. (And keep in mind that TACT is just one in the face of several prior studies all of which were negative). Moreover we all know the hazards of subgroup analysis.

But more telling is a look at the peculiarities of TACT itself. With the publication of the original study in JAMA there was a companion editorial by Dr. Steve Nissen that was appropriately critical. He said:

Execution of a high-quality RCT requires skilled investigators and study coordinators who understand these critical scientific principles. For TACT, more than 60% of patients were randomized at enrolling centers described as complementary and alternative medicine sites. Many of these centers have websites that describe their services, which include an array of unproven therapies ranging from stem cell therapy to regrow breasts after mastectomy, high-dose intravenous vitamin C to treat cancer, and use of cinnamon for treating diabetes to treatment of influenza with antimicrobial essential oils or homeopathic remedies (while warning patients not to undergo immunization). Other sites offer chelation to treat or cure a variety of conditions including autism in children. A common theme of these centers is evident—they appear to attempt to appeal to vulnerable patients who have challenging diseases by offering a variety of unscientific and unproven therapies. Whether a high-quality RCT can be performed at such sites is questionable.

For an in depth look at what Nissen was referring to this article by Atwood and colleagues is a must read. It reviews prior negative studies and exposes what was really going on with TACT and, I believe, is prerequisite to understanding the findings. It's compelling reading and what you get from it is that TACT was badly (and in my reading of the paper, hopelessly) flawed. That's why I ask in title of this post how far the apple of the diabetes substudy can fall from the tree of TACT.

What's the take-home message? Here's Dr. John's:

It would be a huge mistake to dismiss this science because chelation does not conform to preconceived notions or because it is practiced outside the mainstream of medicine. Let's not forget about the patients with this terrible disease. It's not as if we have good treatments for them.

The authors have completely and thoroughly answered all questions posed to them. The trial has been repeatedly inspected and vetted in two prestigious peer-reviewed journals. Both the critics and TACT authors agree that it is too early to recommend chelation therapy. But surely the signal of benefit is strong enough to warrant confirmatory trials. It is time to replicate these findings.

I agree with him that this represents insufficient evidence to change practice. I also agree we shouldn't dismiss something just because it's outside mainstream. But the concerns about TACT are more basic. They are about ethics and scientific standards. My take on the study is not as optimistic as Dr. John's.

Not only was TACT just one positive trial in the face of several negative studies (a Bayesian analysis, I suspect, would be unfavorable) but it was an anomaly. It's hard to read the Atwood paper and not come away thinking this trial was uniquely flawed. Whether the findings of the TACT substudy even warrant further research could be vigorously debated.

Lactate monitoring in critical illness

Free full text review.

Gastric antral vascular ectasia (GAVE)

Here is a case report and mini-review.

Disease associations include cirrhosis and rheumatic diseases particularly systemic sclerosis. The terminology surrounding GAVE tends to be confusing. Watermelon stomach is a subtype of GAVE associated more with the rheumatic diseases. Portal hypertensive gastropathy, with which GAVE may be confused, is a separate entity.

The Avandia hype: cooler heads prevail

As reported in Medscape:

The US Food and Drug Administration (FDA) is lifting restrictions on the prescribing and use of the diabetes drug rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline) on the basis of recent data that demonstrate no elevated cardiovascular risk.

"Although some scientific uncertainty about the cardiovascular safety of rosiglitazone medicines still remains, in light of the new re-evaluation of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, our concern is substantially reduced," the FDA said in a statement.

Finally a more sober assessment. The issue of Avandia and cardiovascular disease was hyped in 2007 when this meta-analysis came out. I tried to apply some perspective but in no time the hype took on a life of its own.

One of the authors of the meta-analysis (Dr. Steve Nissen) didn't seem to mind. In fact, he threw a little fuel to the fire, saying in an interview that Avandia deaths would dwarf the carnage of 911. And his meta-analysis didn't even show a statistically significant increase in deaths attributable to Avandia.

The potential for macrovascular harm from older diabetes drugs had been known for decades but was never hyped in this manner. The screaming was so loud it was hard to have a nuanced discussion though I tried, here and in other posts.

Don't abandon didactic instruction just yet

Didactic instruction was better than computer based learning in this study involving UCLA med students.

123radiology

A series of radiology teaching videos.

Type of bundle branch block and incident risk of heart failure

From a report in Circulation: Heart Failure:

Methods and Results—Cox’s regression was used to evaluate hazard ratios with 95% confidence intervals for HF among 65 975 participants of the Women’s Health Initiative (WHI) study during an average follow-up of 14 years…

Compared with women with no BBB, LBBB, and intraventricular conduction defect were strong predictors of incident HF in multivariable-adjusted risk models (hazard ratio, 3.79; confidence interval, 2.95–4.87 for LBBB and hazard ratio, 3.53; confidence interval, 2.14–5.81 for intraventricular conduction defect). RBBB was not a significant predictor of incident HF in multivariable-adjusted risk model, but the combination of RBBB and left anterior fascicular block was a strong predictor (hazard ratio, 2.96; confidence interval, 1.77–4.93). QRS duration was an independent predictor of incident HF only in LBBB, with more pronounced risk at QRS greater than or equal to 140 ms than at less than 140 ms. QRS nondipolar voltage (RNDPV) was an independent predictor in both RBBB and LBBB and, in addition, in LBBB, QRS/STT angle and ST J-point depression in aVL were independent predictors.

IgA nephropathy

Reviewed in NEJM.

The Sunshine Act: What’s it all about?

Here’s a nice free full text summary in NEJM explaining its effects on physicians. The article mentions ways physicians can participate in the process and further the cause of transparency. If you really want to get on board with transparency here’s the Facebook challenge: next time you attend a drug company sponsored event, check in. Mention that you are attending a sponsored event and include a brief description of the food and beverages.

Prone ventilation in severe ARDS

Up until publication of this study in NEJM prone positioning was reserved as a rescue modality. This study however showed a robust improvement in mortality when prone ventilation was used selectively for patients defined physiologically as having severe disease.

Fungal meningitis following epidural steroid injections

Here are two recent reports from NEJM about the outbreak, traced to a compounding pharmacy [1] [2].

Of interest:

61 deaths were reported.

Strokes, mainly posterior circulation territory, were reported as complications.

This was the largest outbreak of health care related infection ever reported in the US.

Two organisms, Aspergillus fumigatus and Exserohilum rostratum, were identified in clinical infections.

Fungal infections of the CNS may be prone to chronicity and relapse, so final outcomes remain unknown in many patients.

Can we prevent ARDS?

According to a recent review prevention is based on early recognition and management of risk factors. Consideration of certain risk factors suggests various preventive strategies, most of which are not based on high level evidence:

Low tidal volume mechanical ventilation
This is of proven benefit for patients with established ARDS who require invasive mechanical ventilation. What about mechanically ventilated patients who do not have ARDS? The review cites evidence that in such patients it is an effective strategy. This evidence has been accumulating for awhile and I summarized it back in 2010.

Prophylactic PEEP
Although “5 of PEEP” is almost a default setting for mechanically ventilated patients these days the evidence on whether it prevents lung injury is mixed.

Fluid management
Direct evidence is not available concerning fluid management as a preventive strategy. If the cutoff for defining ARDS is arbitrary and lung injury exists along a continuum, one might infer benefit based on findings in patients with established ARDS. It is well known that a conservative fluid strategy is beneficial in such patients.

Appropriate sepsis care
Sepsis is a well known precursor to ARDS. Although the particular outcome of ARDS has not been specifically examined, early application of the sepsis bundle is known to improve general outcomes. ARDS is sometimes a late consequence of sepsis. Halting the sepsis progression early might be a preventive measure.

Transfusion strategies
No such strategies have been studied in controlled trials for prevention of ARDS. However, given the increased recognition of transfusion associated lung injury (TRALI), a restrictive transfusion strategy, as is now generally recommended for hospitalized patients, is appealing.

Altitude related illness

The topic was recently reviewed in NEJM.

High altitude pulmonary edema, acute mountain sickness and high altitude cerebral edema were discussed. High altitude cerebral edema is a serious condition which can be fatal, and exists on a continuum with acute mountain sickness.

HbA1c, QTc and mortality in DM2 patients with foot ulcers

In this study A1c levels below 7.5 and long QT intervals were associated with increased mortality. There is a poorly understood association between lengthened QT interval and DM which I have cited in previous posts.

Langerhans cell histiocytosis

This mysterious and somewhat rare condition was formerly given a variety of confusing names. Here is an update.

Atrial fibrillation decision support

With newly available agents the decision making process is more complex. Here is a web based decision support tool.

Emerging echinocandin resistance in Candida glabrata

From a recent report:

Results. Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19–58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence.

Conclusions. Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.

Species based therapy of candida infections may no longer be enough.

Novel (target specific) oral anticoagulants: pharmacokinetics and drug interactions

This post contains some more of the key points from Dr. Tracy Minichiello's talk at the recent UCSF Hospital Medicine conference along with additional material I've gathered including this review.

First a little background about CYP3A4 and P glycoprotein. CYP3A4 is an important enzyme affecting drug bioavailability and metabolism. Drugs (including the TSOACs) and food (notably grapefruit) may interact via CYP3A4. Unfortunately comprehensive lists of interacting drugs are difficult to find and popular consumer resources may not be updated concerning the TSOACs. I did find this article helpful (click on the pdf link for free full text). It is a bit dated but does contain a long list of applicable drugs. Given the lack of current and comprehensive references your best bet may be to use one of the on line interaction checkers such as the one available via UpToDate.

P glycoprotein is the other big player. P glycoprotein is an ATP-binding cassette (ABC) transporter which extrudes substances out of cells and thus plays a role in drug disposition and bioavailability. All three currently approved TSOACs are susceptible to interactions involving the protein. Again, because comprehensive lists of interacting drugs are not readily available the use of an interaction checker may be necessary. Some background can be found in this paper.


Below are a few of the basics about the kinetics of available TSOACs.


Routes of elimination:

Dabigatran (Pradaxa) 80% renal
Rivaroxaban (Xarelto) 30-60% renal (60% total but half of this is of an inactive metabolite).
Apixaban (Eliquis) 25% renal


Degree of protein binding:

Dabigatran (Pradaxa) 33% (HD effective for removal)
Rivaroxaban (Xarelto) 95% (HD ineffective for removal)
Apixaban (Eliquis) 87% (HD ineffective for removal)


Drug interactions:

Dabigatran (Pradaxa) Via P glycoprotein
Riaroxaban (Xarelto) Via P glycoprotein and CYP3A4
Apixaban (Eliquis) Via P glycoprotein and CYP3A4


Though focused on pulmonary embolism this review is also helpful concerning some of the general aspects of the pharmacokinetics and pharmacodynamics of TSOACs.

Ventilators: how they work, how to use them

Basic Of Mechanical Ventilation from Dang Thanh Tuan

Novel oral anticoagulants

---which by the way are now referred to as the target specific oral anticoagulants (TOACs)---were the topic of the first talk at the UCSF Hospital Medicine course. Tracy Minichiello, MD, Professor of Medicine at UCSF, covered some pearls and practical aspects of using these agents.

Here I will provide a few basic points about the labeling from her talk along with some additional information from external links.

The agents approved in the US are dabigatran (Pradaxa), rivaroxaban (Xarelto) and Apixaban (Eliquis). All three are approved for non valvular atrial fibrillation. Xarelto has the additional approved indications of VTE prevention and treatment. Elimination is 80% renal for Pradaxa, 30-60% renal for Xarelto and 25% renal for Eliquis.

Renal labeling for Eliquis is unusual and applies only if one of two other characteristics is present:

age greater than or equal to 80 years

body weight less than or equal to 60 kg

serum creatinine greater than or equal to 1.5 mg/dL

No data are available for patients with clearance below 15 or on HD.


Renal labeling for Xarelto is problematic because it is complex (varying significantly based on which indication) and is not contained in its entirety in some readily available references (eg Micromedex and Rxlist). The creatinine clearance cutoff below which use is contraindicated is 30 for for VTE treatment and prevention and 15 for a fib. For VTE treatment or prevention no renal adjustment is called for within the allowable range of renal function though for VTE prevention (only) at clearance of 30-50 the labeling says “use with caution.” (Does that mean we throw caution to the wind for other indications?). For a fib with clearance of 15-50 reduction to 15 mg daily is called for.

Adjustment of Pradaxa to half dose (75mg bid) is recommended for clearance of 15-30. More aggressive renal adjustment recommendations apply if certain interacting drugs are administered. See product labeling for those details. As with Eliquis, no information is available for patients with clearance below 15 or on HD.

Labeling for interacting drugs as well as other practical aspects of the use of TSOAC drugs covered in Dr. Minichiello's talk will be discussed in subsequent posts.

At first glance the TSOACs look like “cleaner” drugs with greater ease of use as compared to warfarin. What I learned from Dr. Minichiello's talk and break out session is that this is not necessarily true despite some advantages. You need to know a great deal about the pharmacokinetics of these agents in order to use them confidently and competently.

The Mediterranean diet protects against CKD

I never cease to be amazed. From a recent report:

Results Compared with low adherents, medium and high adherents were 23% and 42% less likely to have CKD, respectively (adjusted odds ratio [95% confidence interval]=0.77 [0.57 to 1.05] and 0.58 [0.38 to 0.87], respectively, P for trend=0.04). Among those individuals with CKD, phosphate intake and net endogenous acid production were progressively lower across increasing adherence groups. No differences were observed regarding other cardiometabolic risk factors across adherence groups. As many as 168 (33%) CKD individuals died during follow-up. Compared with low adherents, proportional hazards regression associated medium and high adherents to a 25% and 23% lower mortality risk, respectively (adjusted hazard ratio [95% confidence interval]=0.75 [0.52 to 1.06] and 0.77 [0.44 to 1.36], respectively, P for trend=0.10). Sensitivity analyses showed significant and stronger associations when only adequate dietary reporters were considered.

Conclusions Adherence to a Mediterranean dietary pattern is associated with lower likelihood of CKD in elderly men. A greater adherence to this diet independently predicted survival in those patients with manifest CKD. Clinical trials are warranted to test the hypothesis that following such a diet could improve outcomes (independent of other healthy lifestyles) in CKD patients.

Improve hospitalists' working conditions, see quality improvement

Medical directors take note.

Hospital medicine CME

Today I'm in San Francisco having just completed UCSF's 17^th Annual Hospital Medicine course. First a shout-out to Bob Wachter, course director, for putting together another great meeting. Offerings of this quality are getting harder to find because for the last decade they have been under attack by the CME thought police. The CME thought police operate under several wrong headed assumptions a few of which I'll mention here:

Industry sponsored CME is corrupt and can't be good. This meeting is one of many counter examples.

CME should not take place in a nice relaxing setting. Resort-based CME is now considered a no-no by many institutions which have discontinued their off campus activities.

CME is only worthwhile if it can be tied in a measurable way to physician behavior. And a close corollary..

Didactic CME should be abandoned because it cannot be linked directly to measurable outcomes. Though the benefits of traditional didactic CME are not as concrete as the thought police would like my own career long learning experience strongly convinces me of its value.

Many attendees Tweeted the conference. I was not among them. For me Tweets are a little too sound-bitey to do justice to the course content. But unlike the CME thought police I respect differences in learning needs among individuals and make no presumption about what style of information sharing is best for others. So if Tweets work for you search #UCSFMHP13 and find Tweets aplenty from the conference.  I may blog portions of the content once I have some down time if I'm still as pumped up and expansive as I am now.

Inverse relationship between length of stay and readmission rate for heart failure

From a report in Circulation: Heart Failure:

Patients treated in countries with longer lengths of stay for heart failure hospitalizations had significantly lower rates of readmission within 30 days of randomization. Findings were similar among sites in the United States, where each 1-day increase in the mean length of stay at the site level was independently associated with a lower risk of all-cause and heart failure readmission.

The authors cite the unintended consequences of DRGs:

Since 1984, when the current reimbursement model was introduced in the United States, there have been strong incentives to reduce lengths of stay to maximize hospital profitability. The consequent reduction in hospital lengths of stay has been accompanied by increases in postdischarge readmission rates,17 which may have resulted in greater overall costs among patients with heart failure.

Strategies associated with reduced heart failure readmissions

From a recent study:

Strategies that were associated with lower hospital RSRRs included the following: (1) partnering with community physicians or physician groups to reduce readmission (0.33% percentage point lower RSRRs; P=0.017), (2) partnering with local hospitals to reduce readmissions (0.34 percentage point; P=0.020), (3) having nurses responsible for medication reconciliation (0.18 percentage point; P=0.002), (4) arranging follow-up appointments before discharge (0.19 percentage point; P=0.037), (5) having a process in place to send all discharge paper or electronic summaries directly to the patient’s primary physician (0.21 percentage point; P=0.004), and (6) assigning staff to follow up on test results that return after the patient is discharged (0.26 percentage point; P=0.049).

H7N9 influenza: are we close to a pandemic?

According to this analysis in BMC Medicine the human-to-human transmission efficiency is below the threshold. A decline in the growth of cases has followed closure of live bird markets.  

Combining esmolol and nor epi in septic shock?

Recently published in JAMA:

Importance  β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects...

Results  Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was −28/min (IQR, −37 to −21) for the esmolol group vs −6/min (95% CI, −14 to 0) for the control group with a mean reduction of 18/min (P less than .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, −1 to 10) vs 1 mL/m2 for the control group (IQR, −3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, −2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was −0.1 mmol/L (IQR, −0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, −0.3 for 0.6; P = .007); for norepinephrine, −0.11 μg/kg/min (IQR, −0.46 to 0.02) for the esmolol group vs −0.01 μg/kg/min (IQR, −0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P less than .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P less than .001).

Conclusions and Relevance For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.

This is very promising but I'm not ready to try it at home, just yet. Yes, it does warrant further study.

More discussion at Medpage Today.

Beverage choice and the risk of kidney stones

From a recent paper:

Results The analysis involved 194,095 participants; over a median follow-up of more than 8 years, 4462 incident cases occurred. There was a 23% higher risk of developing kidney stones in the highest category of consumption of sugar-sweetened cola compared with the lowest category (P for trend=0.02) and a 33% higher risk of developing kidney stones for sugar-sweetened noncola (P for trend=0.003); there was a marginally significant higher risk of developing kidney stones for artificially sweetened noncola (P for trend=0.05). Also, there was an 18% higher risk for punch (P for trend=0.04) and lower risks of 26% for caffeinated coffee (P for trend less than 0.001), 16% for decaffeinated coffee (P for trend=0.01), 11% for tea (P for trend=0.02), 31%–33% for wine (P for trend less than 0.005), 41% for beer (P for trend less than 0.001), and 12% for orange juice (P for trend=0.004).

Conclusions Consumption of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas consumption of coffee, tea, beer, wine, and orange juice is associated with a lower risk.

What's unhealthy about obesity?

Inflammation, mainly. This fascinating article discusses inflammation as a key determinant of unhealthy versus healthy obesity and its role in driving all the nasty components of the metabolic syndrome.

H7N9 influenza: what we know so far

The Annals of Internal Medicine recently reviewed the topic.

Points made in the review:

The virus produces severe disease.

Population immunity is unlikely.

It appears to be sensitive to commonly available antiviral agents.

Human to human transmission potential is unknown.

Hypertension in the ICU

This review discusses definitions of acute hypertensive syndromes, the relevant pathophysiology and treatment approaches.

The antibiotic development pipeline for gram negative infections: how's it going?

According to the recent report from IDSA (free full text) there's been some progress but not nearly enough. There are a few drugs in phase 3 trials but they do not address all the emerging threats.

Antiarrhythmic drugs for resuscitation from cardiac arrest

A recent systematic review and meta-analysis took another look. New research has not changed what we've known for years:

Ten randomized controlled trials and seven observational trials were identified. Amiodarone (relative risk (RR), 0.82; 95% confidence interval (CI), 0.54 to 1.24), lidocaine (RR, 2.26; 95% CI, 0.93to 5.52), magnesium (RR, 0.82; 95% CI, 0.54 to 1.24) and nifekalant were not shown to improve the survival to hospital discharge compared with placebo, but amiodarone, lidocaine, and nifekalant were shown to be beneficial to initial resuscitation, assessed by the rate of return of spontaneous circulation and survival to hospital admission, with amiodarone being superior to lidocaine (RR, 1.28; 95% CI, 0.57 to 2.86) and nifekalant (RR, 0.50; 95% CI, 0.19 to 1.31). Bretylium and sotalol were not shown to be beneficial.

Metabolic syndrome increased the risk for progression to ESRD

---in patients with stage 3 or 4 CKD in this study.

Practical aspects of the novel oral anticoagulants

Here's some more info form a review in CCJM.

Biphosphonates and the risk of atrial fibrillation

From a recent study in Chest:

Results: Six observational studies (n = 149,856) and six RCTs (n = 41,375) were included for analysis. On pooling observational studies, there was an increased risk of AF (OR, 1.27; 95% CI, 1.16-1.39) among bisphosphonate users. Further, analysis of RCTs revealed a statistically significant increase in the risk of serious AF (OR, 1.40; 95% CI, 1.02-1.93) and no increase in the risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates.

Conclusions: Evidence from RCTs and observational studies suggests a significantly increased risk of AF requiring hospitalization, but no increase in risk of stroke or cardiovascular mortality, with the use of bisphosphonate.

Pharmacologic treatments in ARDS

Neuromuscular blocking agents, corticosteroids and nitric oxide, among other agents, are discussed in this review.

The use of neuromuscular blocking agents was systematically studied and found to be beneficial early in the course of ARDS, for 48 hours, in this trial. The study population consisted of patients with a pO2 to FiO2 ratio of below 150. Ventilator mechanics and oxygenation were improved. Mortality benefit was confined to patients with a ratio of below 120. Prolonged post treatment paresis was not observed more frequently in the treatment group. This result was supported in a meta-analysis. UpToDate considers neuromuscular blockade potentially beneficial in severe disease, probably safe when used within limitations as illustrated by recent clinical trials but not recommended for routine use and in need of further study.

Inhaled nitric oxide may buy some time as a rescue modality but has not been shown to improve clinical outcomes.

Corticosteroids have been considered in a variety of situations in both early and later stages of ARDS, and remain controversial. At present the only clearly established role is in specific steroid responsive conditions (e.g. acute eosinophilic pneumonia) causing ARDS.

The use of biomarkers to guide antimicrobial therapy

Many biomarkers have been looked at. For adult hospitalized patients procalcitonin is the most promising. An evidence summary is contained in two companion articles, here and here.

Dietary determinants of incident DM 2

Diets characterized by high Mediterranean diet score and low glycemic load were beneficial in this study.

CT calcium scoring: who and when?

There are a couple of good articles on this topic in a recent issue of CCJM (here and here).

CT calcium scoring has been widely misunderstood by both health professionals and the public for a number of reasons. My own confusion concerned the pathophysiologic rationale. After all we were taught that calcification of atherosclerotic plaques was characteristic of advanced coronary artery disease, right? Moreover it was all too often the young, soft (and presumably non-calcified) plaques, those little blisters on the endothelial lining, that ruptured and caused catastrophic events. How then could calcium imaging be an early detection tool let alone one to assess preclinical risk? Those questions bugged me for a while and had me digging in Big Robbins, Braunwald's Heart Disease and the Path Guy for better answers. I wanted to know exactly when in the pathogenic sequence of atherosclerosis calcification occurred.

It turns out my assumptions were simplistic. Although atherosclerosis may be well underway when calcification occurs, calcium incorporation is not confined to the late stages of the process. Evidently calcium is incorporated before significant stenosis is seen even though considerable plaque maturation may have occurred. This is due in part to the phenomenon of outward remodeling. Moreover, plaques that rupture may be mature plaques but whose fibrous caps have been eroded by inflammatory mediators.

That said, non-calcified plaques can still rupture, making the use of calcium scoring in symptomatic patients problematic, one of the discussion points in the first of the two CCJM articles. Those authors agree with the prevailing view which is that scoring is useful mainly for the screening of asymptomatic patients and has little role in symptom evaluation. Cardiac calcium scoring for symptomatic patients gets little mention in U.S. Guidelines. An older guideline focused on cardiac CT in general gives it no better than a IIb recommendation. The current unstable angina/NSTEMI guidelines, which include evaluation of undifferentiated patients with chest pain, do not recommend it at all.

The second CCJM paper, a companion editorial, takes a more positive view of this controversial use of calcium scoring:

Taken together, these data suggest that the absence of coronary calcification in people at low to intermediate risk indicates a very low likelihood of significant stenotic coronary artery disease and foretells an excellent prognosis.

These data have already been incorporated into the British National Institute for Health and Clinical Excellence (NICE) guidelines, in which calcification scoring is an integral part of the management algorithm in patients with chest pain who are at low risk.

I was initially surprised that the NICE guidelines would embrace it. It's not so surprising on further consideration given that it is cheaper than invasive or noninvasive angiography or stress imaging.

For the more widely accepted indication of asymptomatic screening it is important to keep in mind that the test is considered optional at best. That is, no clinical scenario is given a class I recommendation. Its main advantage in asymptomatic patients is that it will reclassify a fair number of asymptomatic patients who are clinically determined to be at intermediate risk.

Borrelia miyamotoi

---causing an illness resembling human granulocytic anaplasmosis.

Anterior precordial lead ST segment depression in inferior STEMI

Dr. Smith discusses such a case in his ECG blog. He makes some teaching points on various aspects of the case. Concerning the anterior precordial ST depression frequently seen in inferior STEMI we were formerly taught that it signifies “ischemia at a distance,” that is, in the distribution of the left coronary system. That was a myth. We now know that it's the mirror image of posterior STEMI. In fact, as a rule, true ST segment depression does not localize an ischemic process. ST elevation does, T wave inversion does but ST depression does not. It can signify ischemia somewhere but doesn't tell you specifically where.

Universal acetaminophen level screening on all overdoses?

It's easy enough to do but how helpful is it? Results in the literature are mixed. The number needed to screen, depending on the population studied, varies from 45 to over 300. There's an interesting literature review and comment thread at Academic Life in Emergency Medicine.

What happened to unstable angina?

Braunwald and Morrow ask this question in a recent review in Circulation. It seems we’ve gone full circle:

It appears that we have now come full circle in our definition of symptomatic ischemic heart disease. Before the 1930s, 2 manifestations, stable angina and AMI, were recognized. Patients in the gray zone between stable angina and AMI that we now call UA were described 75 years ago and at first appeared to be quite rare. Over the next half-century, they were recognized with increasing frequency, and by 25 years ago, about one half of all patients with NSTE-ACS were considered to have UA. However, use of ever more sensitive biomarkers of myocardial necrosis, especially cTn, has steadily chipped away at the fraction of patients with NSTE-ACS without MI who therefore are still considered to have UA.

In the 70s terms such as “intermediate coronary syndrome” and “pre-infarction angina” were commonplace and conveyed a sense of urgency. The increasing sensitivity of cardiac biomarkers has gradually chipped away at those designations. They have all but vanished now with the advent of the more sensitive troponin assays.

The HDL controversy

This issue was reviewed recently in Cirulation. The HDL story is not over. Some of the points of the review:

The epidemiologic association between low HDL levels and cardiovascular disease is very strong.

The risks associated with low HDL can be moderated by nonpharmacologic means.

The main controversy regarding HDL concerns pharmacologic management. Early studies with niacin (e.g. the Coronary Drug Project) and fibrates (Helsinki I) showed reduction in cardiovascular events. However, several more recently conducted trials failed to show improvement attributable to pharmacologic treatment directed toward HDL. This is in part attributed to confounders such as concomitant statin treatment.

Questions for future and ongoing research include patient selection for treatment and new approaches in the pipeline.

Postural tachycardia syndrome (POTS)

Recent review in Circulation, free full text.

PFO closure for stroke prevention: how does the evidence add up?

Three RCTs had failed to show benefit, so a meta-analysis was done and recently published:

Results

Three RCTs met inclusion criteria. The pooled data provided 2,303 patients, of which 1,150 were in the PFO closure group and 1,153 in the medical therapy group. In the ITT analysis, there were 43 events (3.7%) of the composite end point in the closure group compared with 61 events (5.3%) in the medical therapy group, with a trend in favor of the PFO closure (OR = 0.70; 95% CI, 0.47–1.05, P = 0.08). The incidences of TIA, ischemic CVA, and bleeding were not statistically different between the groups. There was a trend for the more frequent occurrence of atrial fibrillation in the PFO closure group (OR = 3.29; 95% CI, 0.86–12.60, P = 0.08). In the AT analysis, the composite end point was significantly less frequent in the PFO closure group (OR = 0.62; 95% CI, 0.41–0.94, P = 0.02).

Here is a discussion of the article at Medpage Today.

This will be spun various ways. My summation is that while the evidence is inconclusive and no one can make a high level claim for closure over medical therapy the as treated analysis suggests that patients who successfully completed device therapy did better. The true practice of evidence based medicine in this situation will require a nuanced conversation with the patient. Statements like “we need to fix this hole in your heart to keep you from having another stroke” are unfounded. Dismissive statements like “PFO closure doesn't work” only reflect one's misunderstanding of the proper application of EBM.

The prevention of stroke in patients with PFO is, to say the least, controversial. It would seem plausible for device therapy to be superior to medical treatment and for systemic anticoagulation over antiplatelet therapy though neither has been proven convincingly. The UptoDate authors “suggest” medical over device therapy and “suggest” antiplatelet therapy over anticoagulation unless there is a specific reason to favor anticoagulation in the individual patient.

Management of acute pancreatitis: can we be evidence based?

Evolving concepts and controversies are addressed in a recent review published in the Cleveland Clinic Journal of Medicine. The article is available as free full text. A few take home points will be mentioned here.

The optimal timing of CT scanning is based on the fact that the yield for detecting necrosis is relatively poor until 72 hours or so after presentation. Earlier scanning may be indicated in certain clinical circumstances suggestive of complications. Scanning at the time of presentation is justified if the diagnosis is unclear. That is to say that CT scanning provides just one of the three diagnostic criteria, the other two being clinical and laboratory. If those two are present CT is not necessary to make the diagnosis.

There has been a gradual shift in thinking about severity assessment. While prognostic assessment may be helpful in anticipating complications, advising patients and assembling resources it may not be as useful in an algorithmic approach to management as once thought. For example, a clinical determination of severe pancreatitis defines the patient as having pancreatic necrosis. In the traditional view that would be an indication for antibiotic therapy. But that thinking is not supported by evidence and no longer holds sway. In addition, the role of severity assessment as a target for fluid resuscitation is unclear. Traditional thinking held that assessment of pancreatitis as severe targeted patients for more aggressive initial fluid administration. A study form 2011 by Warndorf and colleagues, however, found the opposite: it was the patients with milder (so called “interstitial”) pancreatitis who benefited most, suggesting that the window of opportunity is lost once pancreatitis progresses to severe.

There are many clinical tools available for severity assessment. Traditional tools (e.g. Ranson) are falling out of favor because they require observation over time and cannot classify patients within the first 24 hours. Some more recently validated methods, particularly the SIRS determination, are simpler to use and enable severity assessment on the front end.

Current concepts in fluid resuscitation have become more nuanced. The traditional view of “more is better” was based mainly on theory, animal data and low level human studies. Despite those limitations it held sway until challenged a couple of years ago by a study I cited here. According to that study fluids in excess of 4.1L in the first 24 hours were associated with harm. The thinking is shifting from “the more the better” to “shoot for the optimum.” Under resuscitation may lead to pancreatic ischemia at the microcirculatory level triggering necrosis, mediator release, SIRS, vascular collapse and distant organ failure. Too much fluid on the other hand may lead to organ congestion and compartment syndrome.

In addition, fluid resuscitation should be front loaded. The Warndorf paper reported that patients given greater than one third the 72 hour total volume in the first 24 hours had better outcomes. Of note, that group also had lower total 72 hour volumes.

As to the actual amount to give, the CCJM review says:

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

The way to accomplish this in an average sized individual is to front load in the first several hours. Such a protocol was described in a 2011 paper by Wu and colleagues. It is based on an aggressive initial bolus followed by high volume maintenance fluid rates for the first few hours but then calls for a sharp reduction in IV rate if the BUN comes down a bit at either of two lab checkpoints starting around 8 hours following presentation. Patients treated according to that protocol received less total fluid than those who were not and the total amount received came fairly close to the upper range recommended in the CCJM review. Outcomes were not improved with use of the protocol but the patient numbers were small. What was found was that patients treated with lactated Ringer's did better than those treated with saline whether on or off protocol. Again the numbers were small and the outcomes were soft: SIRS and CRP.

Though based only on physiologic rationale (lower microcirculatory pH in the pancreas is believed to activate enzymes and promote inflammation) and the one small study with soft endpoints the CCJM review recommends LR over saline.

Additional discussions in the review focus on nutrition (enteral is better than parenteral, NG is as good as jejunal, and enteral nutrition reduces infection), compartment syndrome (an emerging concern in pancreatitis) and the management of walled off necrosis and fluid collections.

FFP versus 4 factor PCC for warfarin reversal

4 factor PCC was associated with faster INR reversal, a lower red cell transfusion requirement and a better safety profile in this study.

Note that PCC is favored over FFP in the latest ACCP guidelines.

Treatment of ventricular arrhythmias in the post-CAST era: beyond device therapy

Some take home points from a recent review:

The CAST study changed our thinking about drug treatment of ventricular arrhythmias but it did not eliminate the practice altogether.

Drug treatment of ventricular arrhythmias is not indicated for prevention of sudden cardiac death but two indications remain: symptom control and prevention or treatment of tachycardia induced cardiomyopathy.

PVC burdens of more than 15% of heart beats as well as frequent runs of VT, even if asymptomatic, have been associated with the development of tachycardia induced cardiomyopathy.

There has been a shift toward safer drugs (e.g. beta blockers).

Some of the outflow tract and fasicular ectopic rhythms are amenable to ablation.

Outflow tract and fasicular tachycardias have characteristic morphology and their sites of origin can often be identified on the surface electrocardiogram.

Renal Denervation as a treatment for resistant hypertension

This is gaining enthusiasm, devices are proliferating and research is ongoing. Free full text review here via Medscape. More data are needed to answer concerns about renal function decline related to the procedure and the durability of antihypertensive effect.

More information on azithromycin and the risk of sudden cardiac death

This CCJM review covers many of the same points I recently blogged here.

The role of obesity in atrial fibrillation

Atrial fibrillation is increasingly being recognized as a disease of obesity and the metabolic syndrome. A nice review (free full text) on the topic was recently published. Background here.

Systemic sclerosis review

This review, available in free full text from Mayo Clinic Proceedings, is the best I've seen on this topic. Points I found interesting:

The traditional classification of SS into diffuse and limited (aka scleroderma vs CREST) is simplistic. Finer gradations based on the extent of skin involvement or rate of progression of skin disease may be more meaningful. Also, specific disease profiles based on auto antibody associations are emerging. Antibody-phenotype associations are shown in one of the tables in the article. Although the associations are not absolute (and there is a certain amount of overlap) the specific antibodies are fairly predictive such that antibody profiling early in the course of the disease is beneficial.

There are four pathophysiologic dimensions to SS: vasospasm, obliterative vasculopathy, tissue fibrosis and autoimmunity.

There is no “treatment for SS” per se. Treatment is directed at disease manifestations. Immunosuppression directed against autoimmune processes that drive certain clinical manifestations is recommended in selected circumstances but none of it is supported by high level data.

Corticosteroids, in disfavor because they increase the risk of renal crisis, should be used sparingly if at all.

Novel anticoagulants versus LMWH for VTE prophylaxis in orthopedic patients

A systemic review in the Annals of Internal Medicine:

Data Synthesis: Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin, aspirin, or unfractionated heparin.

Limitations: Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice.

Conclusion: New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding.