Wednesday, May 20, 2015

Folic acid for primary stroke prevention


From the CSPPT RCT:

Design, Setting, and Participants The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20 702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study.

Interventions Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10 348) or a tablet containing enalapril, 10 mg, alone (n = 10 354)...

Results During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril–folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril–folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril–folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril–folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events.

Conclusions and Relevance Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels.

Tuesday, May 19, 2015

Ketoacidosis related to sodium-glucose cotransporter-2 (SGLT-2) inhibitors inhibitors in treatment of type 2 diabetes


As reported in Pharmacy Times, according to a new FDA warning 20 post marketing cases have been cited. Some were ketosis without full blown ketoacidosis. Current drugs in this new class are canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance).

How might these drugs cause ketoacidosis? No mechanism was cited in this report. I can speculate on a few. Because they cause glycosuria, there are a number of consequences that might tip a patient over who has marginal insulin reserve (including patients thought to have type 2 diabetes but who actually have some atypical form). First, glycosuria dumps calories which could cause a catabolic state. In association with this already marginal insulin levels might fall. If the glycosuria results in volume depletion the neurohumoral response is counter regulatory and antagonistic to insulin. Finally, the agents increase the risk for urinary tract infections which might lead to decompensation.

Coronary fractional flow reserve


Monday, May 18, 2015

Revised TPA contraindications in acute ischemic stroke


The labeling changes are summarized here in a post from Emergency Medicine PharmD.

In general the contraindications have eased and there are now vague statements open to wider ranges of interpretation.

Specifically:

“Evidence of intracranial hemorrhage on pretreatment evaluation” has been replaced with “Current intracranial hemorrhage.” The new wording here apparently means the FDA intends a change but it's a mystery to me what the change actually is.

“Suspicion of subarachnoid hemorrhage” has been replaced with “Subarachnoid hemorrhage,” thus ignoring the slight possibility that a patient with a sudden severe headache could have SAH despite a negative CT. Has the FDA decided this is a chance worth taking? After all, no one is going to do an LP before treating with TPA.

Prior stroke (implied in the old labeling to have been within three months) has been eliminated from the contraindications.

“Intracranial neoplasm, arteriovenous malformation, or aneurysm” is replaced with “Presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms),” implying that there may be other intracranial contraindicating conditions and some neoplasms that are not contraindications.

A list of specific coagulopathies and contraindicating antithrombotic drugs has been replaced by the term “Bleeding diathesis.”

The specific blood pressure contraindication has been replaced by the general statement “Current severe uncontrolled hypertension.”

Seizure at presentation and history of intracranial hemorrhage have been eliminated from the contraindications.


Treatment of iron deficiency with oral supplements


A nice overview at ClinicalCorrelations.

Sunday, May 17, 2015

Extra-intestinal C diff



Overall, 40 patients with extraintestinal CDI were identified: 25 had abdominopelvic infections, 11 had bloodstream infections, 3 had wound infections, and 1 had pulmonary infection. C difficile was isolated with other organisms in 63% of cases. A total of 85% of infections were nosocomial. Factors associated with extraintestinal CDI included surgical manipulation of the gastrointestinal tract (88%), recent antibiotic exposure (88%), malignant tumors (50%), and proton pump inhibitor use (50%). Diarrhea was present in 18 patients (45%), 12 of whom had C difficile polymerase chain reaction (PCR)–positive stool samples. All isolates tested were susceptible to metronidazole and piperacillin-tazobactam. Management included both antimicrobial therapy and guided drainage or surgical intervention in all but one patient. The infection-associated mortality rate was 25%, with death a median of 16 days (range, 1-61 days) after isolation of C difficile.

Saturday, May 16, 2015

Drug induced thrombotic microangiopathy


From a systematic review in Blood:

Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA.

Friday, May 15, 2015

A systematic review of reperfusion strategies for stroke



Evidence Review Systematic literature search of MEDLINE databases published between January 1, 1990, and February 11, 2015, was performed to identify studies addressing the role of thrombolysis and mechanical thrombectomy in acute stroke management. Studies included randomized clinical trials, observational studies, guideline statements, and review articles. Sixty-eight articles (N = 108 082 patients) were selected for review.

Findings Intravenous thrombolysis is the mainstay of acute ischemic stroke management for any patient with disabling deficits presenting within 4.5 hours from symptom onset. Randomized trials have demonstrated that more patients return to having good function (defined by being independent and having slight disability or less) when treated within 4.5 hours after symptom onset with intravenous recombinant tissue plasminogen activator (IV rtPA) therapy. Mechanical thrombectomy in select patients with acute ischemic stroke and proximal artery occlusions has demonstrated substantial rates of partial or complete arterial recanalization and improved outcomes compared with IV rtPA or best medical treatment alone in multiple randomized clinical trials. Regardless of mode of reperfusion, earlier reperfusion is associated with better clinical outcomes.

Conclusions and Relevance Intravenous rtPA remains the standard of care for patients with moderate to severe neurological deficits who present within 4.5 hours of symptom onset. Outcomes for some patients with acute ischemic stroke and moderate to severe neurological deficits due to proximal artery occlusion are improved with endovascular reperfusion therapy.

I wonder how the TPA cynics will knock this one down.

Tuesday, May 12, 2015

Return of consciousness during CPR



Methods

The databases Medline, PubMed, EMBASE, Cinahl and the Cochrane Library were searched from their commencement to the 8th July 2014. We also searched Google (scholar) for grey literature. We combined MeSH terms and text words for consciousness and CPR, and included studies of all types.

Results

The search yielded 1997 unique records, of which 50 abstracts were reviewed. Nine reports, describing 10 patients, were relevant. Six of the patients had CPR performed by mechanical devices, three of these patients were sedated. Four patients arrested in the out-of-hospital setting and six arrested in hospital. There were four survivors. Varying levels of consciousness were described in all reports, including purposeful arm movements, verbal communication, and resuscitation interference. Management strategies directed at consciousness were offered to six patients and included both physical and chemical restraints.

Monday, May 11, 2015

The twenty five year experience with cardiac sarcoid in a nationwide study



Background—This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland...

A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased greater than 20-fold during the 25-year period, reaching 0.31 in 1×105 adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×105. Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction less than 50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan–Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%.

Sunday, May 10, 2015

In isolated right sided heart failure don't forget carcinoid heart disease



Retrospectively, clues to the presence of carcinoid heart disease include thickening of both the tricuspid and pulmonic valve leaflets by echocardiogram, a pressure gradient, albeit small, across the pulmonic valve, the plastering of the septal tricuspid-valve leaflet to the ventricular septum, the total absence of left-sided heart disease, and the presence of extremely low 12-lead QRS electrocardiographic voltage.


Saturday, May 09, 2015

Blood pressure differential in assessing patients for aortic dissection



Bottom line: Presence of chest pain with blood pressure differential and/or pulse differential should raise clinical suspicion of aortic dissection. There is evidence that the presence of pressure difference greater than 20mmHg is a strong predictor of dissection, but absence of pressure differential should not exclude a diagnosis of aortic dissection.

Klompas M. Does this patient have an acute thoracic aortic dissection?

Thursday, May 07, 2015

Dr. Oz and the resulting media attention to quackademic medicine: flash point or flash in the pan?


Quackademic medicine refers to the teaching and promotion of quackery in medical schools. I became concerned about the trend early in my blogging days and first wrote about it here. It was in a post 3 years later that I coined the term. Though the phrase has since gone viral thanks to Orac and a couple of bloggers over at Science Based Medicine (who have kindly taken care to provide attribution) the general concern of pseudoscience in medical education never got the widespread attention I thought it deserved. Until, perhaps, now, thanks to Dr. Oz. You see, Dr. Oz is both a celebrity in the world of pseudoscience and a faculty member at a prestigious medical school.



A recent spike in blog traffic alerted me to this article in The Atlantic about Dr. Oz. The author, who seems to like the term quackademic medicine, cited me by linking the term to my original post. His perspective is refreshing: it's not so much about Dr. Oz as it is about this sorry, pathetic trend in medical education. He writes:



But despite numerous subsequent think pieces about the man behind the curtain, a crucial question stands out: Why call for Dr. Oz’s dismissal, when many medical schools and hospitals endorse the most outlandish of his claims?



Indeed. The call for Dr. Oz's dismissal came in the form of a letter written by a group of concerned physicians. The author of the Atlantic piece was not the only one questioning the letter. Orac, the blogger at Respectful Insolence, thought that while the letter was correct in its criticism of Dr. Oz it lacked any real purpose other than as a publicity stunt.



Be that as it may, it was much needed publicity in my opinion. If there is a weapon against quackademic medicine it's exposure. Toleration of quackery has become too entrenched in academic medicine for there to be a solution from within.

Over testing by hospitalists


For years hospitalists have been promoted, despite evidence to the contrary, as the ultimate drivers of efficiency and cost savings in health care. This promotion ranges from unproven claims that the hospitalist model delivers equal quality but at lower cost compared to the traditional model to more grandiose ideas. But a new study in the Annals of Internal Medicine reports survey data from 2011, when the hospitalist movement had matured well into its second decade, indicating rampant over testing by hospitalists. From the paper:

Design: National survey of practice patterns for 2 common clinical vignettes: preoperative evaluation and syncope. Respondents were randomly selected and randomly provided 1 of 4 versions of each vignette. Each version contained identical clinical information but varied in factors that could change physician behavior. Respondents were asked to identify what they believed most hospitalists at their institution would recommend in each vignette.

Setting: Mailed survey conducted from June through October 2011...

Results: 68% (1020 of 1500) of hospitalists responded. They reported overuse in 52% to 65% of the preoperative evaluation vignettes and 82% to 85% of the syncope vignettes.

More than that, the responses indicated that the hospitalists ordered these tests despite knowing they were not recommended in the guidelines, patient satisfaction pressure being cited as a big driver.

According to a related piece inToday's Hospitalist, positive cost incentives were not found to be responsible:

Dr. Kachalia points to another interesting result: The study shows that even in settings in which physicians have little to no financial incentive, they still overuse tests.


Distinguishing athlete's heart from hypertrophic cardiomyopathy


Increased chamber dimensions seemed to characterize the athletes in a recent study:


We studied athletes and patients with HC with borderline LV hypertrophy (13 to 15 mm).

Clinical and echocardiographic parameters were compared.

LV cavity less than 54 mm distinguished HC from athlete's heart with the highest sensitivity and specificity.

Athletes were characterized by larger left atria compared with patients with HC.

Also, diastolic functional parameters, electrocardiography, and family history proved useful in the differential diagnosis.


Wednesday, May 06, 2015

Article in The New Yorker on low value health care


Atul Gawande, stylistically, is a great writer. He is also a master at telling stories that bring arcane health policy topics to life. But articles written for popular appeal often lack the nuance that a more scholarly treatment would offer. His article in the New Yorker on low value health care suffers from this problem. While one would hardly disagree with his premise that there is waste and inefficiency in health care the article has its issues.

Although Dr. Gawande talks about research findings in a paper that gave him ideas for the piece, he does not cite or even name it. Annoying. I had to do some searching and finally decided it must be this one. It reported that somewhere between and 25 and 40% of Medicare beneficiaries received at least one test or treatment found on the Choosing Wisely don't do list.

Gawande talks a great deal in the article about value. But value in health care is not as straightforward as he seems to indicate. According to the original meaning of evidence based medicine, value is an individual matter and varies from one patient to another. That's not to say that medical decisions are driven by whatever the patient happens to want. Patients often seek ineffective or even harmful treatments. Evidence based medicine integrates the patient's preferences and values with the expertise of the clinician and the best external evidence. Value is not easily defined nor is it measurable, contrary to what some of our opinion leaders want us to think.

Neither the Choosing Wisely list nor the manner in which many policy leaders would choose to use it is evidence based. That raises the question of whether Gawande himself adheres to EBM. In this article, at least, he makes no pretense of doing so. For many of those who support the popular orthodoxy in today's health care discussion it may be safer to remain silent about EBM because its principles go against much of today's policy agenda for reasons I explained here and elsewhere.

After discussing data showing pervasive waste in U.S. health care, Gawande provides a series of anecdotes to illustrate what it looks like and explain why. Patients think more is better, doctors err on the side of doing more (they don't want to miss anything) and technological advances, which often out pace evidence, drive more interventions. He says this about the incentives in health care:

What explained this? Our piecework payment system—rewarding doctors for the quantity of care provided, regardless of the results—was a key factor. The system gives ample reward for overtreatment and no reward for eliminating it. But these inducements applied everywhere.

No reward for eliminating it? There he's flat out wrong. It's not so simple. Health care in the U.S. has been under a mixed set of incentives, both positive and negative, for decades. Capitated payment plans are widespread and have been around for a long time. Hospitals are paid for inpatient care under the Prospective Payment system in which less testing, less care and shorter hospital stays mean more money. Financial incentives for more care do exist but are only part of the picture. There are multiple and complex reasons for out of control costs and it would be naive to assume that bundled or capitated payments, part of the focus of today's accountable care organizations, will necessarily be effective in the long term.

He goes on to illustrate a short term success story with two accountable care organizations in McAllen, Texas. Whether this success will be sustainable remains to be seen. Managed care in the 1990s operated on similar principles but the initial financial success was short lived. It operated on the premise that the best medical care saves money in the long run. That's the idea behind today's accountable care organizations and seems to be Gawande's view. Although highly integrated, evidence based care should be better and less wasteful than much of what takes place in the U.S. today, the idea that better care is less expensive is unproven. It may in fact be more expensive. Much of the gap between existing care and evidence based care is underutilization. Gawande hints that he realizes this:

But not all quality can be measured. It’s possible that we will calibrate things wrongly, and skate past the point where conservative care becomes inadequate care. Then outrage over the billions of dollars in unnecessary stents and surgeries and scans will become outrage over necessary stents and surgeries and scans that were not performed.

In preparing for this post I asked myself what I would do if I were the czar of an accountable care organization. I think I would follow the motto I once picked up from a wise sage: “tools, not rules.” To the extent I could I would subvert all the artificial performance measures and pathways. I would give doctors all the information resources I could and do my best to provide an environment where they could practice integrated, evidence based care.


Fondaparinux versus low molecular weight heparin (LMWH) in the treatment of NSTEMI


Here's some real world experience reported from a Swedish database:

Design, Setting, and Patients Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40 616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010.

Exposures In-hospital treatment with fondaparinux or LMWH during the hospital stay...

Results In total, 14 791 patients (36.4%) were treated with fondaparinux and 25 825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups.

These findings are somewhat similar to those of OASIS 5 which I referenced here.

It would appear that the improved outcome was driven by a reduction in bleeding with fondaparinux. I think this relates to the fact that for acute coronary syndrome fondaparinux is administered in the same dose as is used for VTE prophylaxis rather than in a full therapeutic anticoagulation dose.