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Archive for May, 2016

Primary Care Corner with Geoffrey Modest MD: FDA Warnings Fluoroquinolones, Aripiprazole, Olanzapine

31 May, 16 | by EBM

By Dr. Geoffrey Modest

The FDA has sent out several Drug Safety warnings in the past few weeks.

  1. Fluoroquinolones
  • Given the widespread reports of adverse effects of fluoroquinolones, the FDA issued a report in 2013 requiring a label change (see http://www.fda.gov/Drugs/DrugSafety/ucm365050.htm ). Specifically, they noted an association with disabling peripheral neuropathy (with the onset of peripheral neuropathy often within a few days of starting the fluoroquinolone, and ongoing symptoms for more than a year in some patients, long after stopping the med).
  • There already were labels warning about risks of tendinitis, tendon rupture, CNS effects, exacerbations of myasthenia gravis, QTc prolongation/torsades, phototoxicity, and hypersensitivity (and I did send one patient to the ICU with anaphylaxis from ciprofloxacin around 15 years ago)
  • The actual warning from 5/12/16 states that the FDA “is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options”. See http://www.fda.gov/downloads/Drugs/DrugSafety/UCM500591.pdf .
  1. Aripiprazole
  • The FDA just issued a safety alert for aripiprazole (goes by trade name Abilify). See http://www.fda.gov/downloads/Drugs/DrugSafety/UCM498825.pdf. This medication has FDA approved indications for treating schizophrenia, bipolar disorder, Tourette’s disorder, and irritability associated with autistic disorder. It is also used (and apparently advertised widely on TV) in combination with antidepressants to treat depression. The FDA is warning that it might be associated with compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex. And these urges desist on stopping the drug or with dose reduction. But 4 cases had a return to this behavior with rechallenge. They do note that these impulse-control problems are rare (184 case reports since 2002, though there are apparently 1.6 million patients on the drug), with pathological gambling being the most common. The recommendation is just that we and patients be alert to this possibility. And we should closely monitor patients at higher risk for impulse-control problems, including personal/family history of obsessive-compulsive disorder, impulse-control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors. But in most cases there was no prior history of compulsive behaviors overall, and none had a history of pathological gambling, compulsive sexual behavior, binge eating, or compulsive shopping prior to taking aripiprazole.
  • On reading about aripiprazole it is quite remarkable the array/diversity of actions it has: (per com) — “Aripiprazole exhibits high affinity for dopamine D2and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors, and moderate affinity for the serotonin reuptake site. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.]” It is certainly true that many CNS-active drugs have multiple effects on multiple neurotransmitters, leading to many of their attendant adverse effects, though aripiprazole outdoes seem to outdo some of the others.
  1. Olanzapine
  • The FDA issued a drug safety communication about olanzapine and DRESS syndrome (see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm500123.htm ).
  • DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) often starts as a rash that spreads to all parts of the body, and includes 3 or more of: rash, eosinophilia, fever, lymphadenopathy, and systemic complications (hepatitis, myocarditis, pericarditis, nephritis, pancreatitis, pneumonitis), and often occurs after a long latency of 2-8 weeks after drug exposure. there is a 10% mortality rate
  • 23 cases of DRESS have been reported since 1996. One patient has died.

 

So, as with all FDA reports, these cases likely significantly underestimate the true incidence of problems, since in a busy clinical session, it is difficult/time-consuming to report the adverse events. But it is important for us as clinicians to know about these potential issues. The most important one for us is the fluoroquinolone advisory. As many blogs and articles have articulated: many too many antibiotics are being used for non-bacterial infections (bronchitis, sinusitis…), and there has been a very unfortunate shift to using more broad-spectrum and resistance-producing antibiotics (more azithromycin for strep, etc., than narrower antibiotics like penicillin). And I think many of us do still use ciprofloxacin for uncomplicated urinary tract infections.

See http://blogs.bmj.com/ebm/2015/08/03/primary-care-corner-with-geoffrey-modest-md-antibiotic-overprescribing-2/ for studies on antibiotic overprescribing and their consequences

Primary Care Corner with Geoffrey Modest MD: A Follow-up on the Primary Care Initiative in UK

27 May, 16 | by EBM

By Dr. Geoffrey Modest

UK report on primary care from the House of Commons Health Committee (http://www.publications.parliament.uk/pa/cm201516/cmselect/cmhealth/408/408.pdf)

Basic issues addressed in the report:

  • Improve access to primary care by extending hours of service, reaching out to those currently disenfranchised by the existing model of care
  • Improve record keeping and access to medical records as a means to improve patient safety, with patient consent for more general access to records
  • Facilitate phone and IT access for patients and for consultations
  • Quality improvement initiatives: Care Quality Commission inspection of primary care practices, helping practices improve
  • Ten-minute appointments do not allow adequate time for safe practice or to address whole person care. Relentless time pressure from short appointments tends to restrict patients to discussing only one problem with their GP and clinicians to working in a reactive rather than proactive manner. Given the increasing complexity of the long term conditions that are managed in primary care, allowing time to provide safe and holistic care must be a priority. We agree with the Primary Care Workforce Commission that reshaping primary care to give patients sufficient time to discuss their conditions with health professionals should be a central aim of the new models of care.”
  • Develop and extend the use of team-based care, including using “physician associates”
  • Increase access to consultant psychiatrists. increase communication with specialists overall by email and messaging
  • Continued vigilance at national and local level to make sure that conflicts of interest are not influencing decisions
  • Significantly increase the number of primary care doctors by attracting more doctors into the field. Look carefully at why doctors quit.
  • Promote primary care in medical schools, including expanding the criteria for med school admissions (e.g., including commitment to providing care to a community, not just purely scientific qualifications), increasing teaching of general practice, and stress that the career is as intellectually rewarding as any specialization
  • Use financial incentives/loan repayment to help place MDs and nurses in areas that historically have had trouble attracting them
  • Many similar approaches as above for attracting and retention of nurses, physician associates, physiotherapists, pharmacists in primary care
  • Look at other funding mechanisms, including capitated payment systems within primary care federations
  • A larger proportion of the health care money should go to primary care
  • Make sure that financial mechanisms reinforce primary care, instead of diverting patients inappropriately to secondary care

So, pretty impressive in many ways. Not only does it reinforce primary care as the crux of the health care system, but it suggests several specific reforms to enable that. Unfortunately, in the US we not only do not have a coherent and integrated system of care with universal access, but we have a system dominated by hospitals and procedure-oriented specialists. Even the move to capitation seems to situate hospitals and not primary care at its center. and the decision-makers for our reimbursement system is dominated by those who make lots of money from procedures (and, as I have said before, injecting a patient for carpal tunnel syndrome or painful joints takes me a few minutes and is not very complex. Taking care of my patient with uncontrolled hypertension, diabetes, etc., who is in an untenable social situation, and is depressed, is really intellectually and emotionally difficult and very time-consuming). But I think the kernel of the current UK initiatives is central to a major reorientation of our health care system (and extending the system to one of universal access is certainly another essential aspect).

Primary Care Corner with Geoffrey Modest MD: Zika Virus Testing

26 May, 16 | by EBM

By Dr. Geoffrey Modest

Zika virus testing: the CDC just published new guidance for testing for the Zika virus (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6518e1.htm?s_cid=mm6518e1_w ):

  • Use real-time reverse transcription-polymerase chain reaction (rRT-PCR) on urine if <14 days after the onset of symptoms in patients with suspected Zika virus disease
  • Use rRT-PCR test on urine and on serum if <7 days after symptom onset
  • Any positive test result provides evidence of Zika infection

Basis of recommendations (details in http://www.cdc.gov/mmwr/volumes/65/wr/mm6518e2.htm?s_cid=mm6518e2_w )

  • rRT-PCR is a rapid test and is highly specific
  • In most patients, the Zika virus RNA is not detected in the serum after the first week of illness
  • Recent report found the rRT-PCR to be positive in the urine for at least 2 weeks after onset of symptoms (in Florida study, from as early as 1st day of symptoms till as late as 20 days later)
  • The Florida study also found that of 66 cases, 61 (92%) had positive urine and 31 (47%) positive blood testing.
  • Within the first 5 days of symptoms, of 55 patients, 52(95%) had a positive urine test and 31 (56%) had a positive blood test
  • >5 days after symptoms, 9 (82%) had positive urine and none had positive serum
  • Of the 53 who had testing at multiple sites: 92% had positive urine, 81% positive saliva, and 51% positive serum

So, urine testing is by far the most sensitive overall, but there are occasional cases of Zika positive only on blood testing.

No change in recommendations on who to test (see http://www.cdc.gov/zika/pdfs/denvchikvzikv-testing-algorithm.pdf ):

  • Persons with 2 or more of: rash, fever, arthalgias or conjunctivitis during or within 2 weeks of return from an area with Zika virus activity, or with a link to a Zika virus infected traveler (sexual partner, household contact, etc.)
  • For CDC guidance for women of reproductive age with possible Zika virus exposure, see http://www.cdc.gov/mmwr/volumes/65/wr/mm6512e2.htm

For recent review on Zika: see http://blogs.bmj.com/ebm/2016/04/27/primary-care-corner-with-geoffrey-modest-md-zika-virus-review/

Primary Care Corner with Geoffrey Modest MD: Medical Errors, and a Plea For Primary Care

25 May, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent brief article looking at the approximate rate of medical errors leading to death, and suggesting that this was the 3rd leading cause of death in the US (see doi: 10.1136/bmj.i2139).

Details:

  • A 1999 Institute of Medicine report, based on the 1984 Harvard Medical Practice Study and the 1992 Utah and Colorado Study, suggested that of the 180,000 reported iatrogenic deaths, 51% were preventable, though the lead Harvard researcher suggested that the number was closer to 78% (i.e. 140,400 preventable deaths). This number was based on a record review of a population-based study of New York Hospitals reported in 1993.Overall there was a 4% incidence of adverse events reported in the hospitalized patients.
  • A 2004 report from the Agency for Healthcare Quality and Research Patient Safety Indicators for the Medicare population estimated 195,000 deaths from medical errors per year (data from 2000-2002). This study found that of 37,000,000 admissions, there was an adverse event rate of 3.1%, a lethal adverse event rate of 0.7%, 389576 preventable deaths over these years, which they extrapolated to 2013 to be 251,454 preventable lethal adverse events.
  • The US Dept of Health and Human Services/Office of Inspector General examined health records of hospital inpatients in 2008, finding 180,000 deaths/year from medical errors in those on Medicare. This study found that of 838 admissions, there was an adverse event rate of 13.5%, a lethal adverse event rate of 1.4%, a 44% rate of preventable deaths, leading to 12 deaths, which they extrapolated to 2013to be 219,579 preventable lethal adverse events.
  • A 2004 study of 3 tertiary care hospitals (2 community-based teaching hospitals, both urban with one in the Mid-west and one Northeast, and one academic hospital in the West) finding that of 795 admissions, there was an adverse event rate of 33.2% (!!!), a lethal adverse event rate of 1.1%, 100% felt to be preventable, leading to 9 deaths, which they extrapolated to 2013 to be 400,201 preventable lethal adverse events
  • A 2002-7 study of 10 hospitals in North Carolina, finding that of 2341 admissions, there was an adverse event rate of 18.1%, a lethal adverse event rate of 0.6%, 63% felt to be preventable, leading to 14 deaths, which they extrapolated to 2013 to be 134,581 preventable lethal adverse events
  • The summary findings were the same as those of the AHRQ/Medicare study, since its 37M admissions so dwarfs the other studies in the weighted average. (So, estimated number of preventable deaths was set at 251,454 for 2013)
  • And, none of these studies included deaths at home, or in nursing homes, or in an ambulatory setting (which is an issue, both in terms of hospitalized patients who may have been discharged from the hospital but may have died relatively shortly thereafter from a hospital-related error, and because some patients undoubtedly die because of errors in medical care in the non-hospital setting itself).

So, there are certainly several issues here:

  • The quality of the data: the list of causes of death, per the CDC, is based on ICD coding, and there are no codes for diagnostic errors, poor judgment, inadequate skills, or, in general, either human or systems errors that could lead to death. And, accurate numbers still assume that the people or the institution involved is willing to acknowledge that a preventable cause of death occurred.
  • It is pretty striking that the number of adverse events was so variable (why was the Medicare one in the 3% range, yet up to 33% in the 3 tertiary care hospitals? Is it how adverse events are classified? Is it that Medicare just wasn’t looking hard enough?), but still, finding up to 1% of admissions were associated with preventable deaths is shocking….
  • There are many methodological concerns with the data in this report:
    • How accurate are the data collected (and how do they define a death as preventable )?
    • How extrapolatable are the data from a survey of 3 or 10 hospitals, or even the Medicare data, to the general population, in teaching and nonteaching hospitals, in small and large hospitals, in urban and rural hospitals, in hospitals with a slew of specialists and not, etc.
    • How extrapolatable is the preventable death rate from 2002 or 2008 to 2013? Lots has changed. Part is that the degree of illness of admitted patients may have changed. Or the intensity of testing. Or doing higher risk procedures. and the extrapolation of preventable deaths to 2013 as done in the above study is based only on the number of admissions in 2013 vs the number in the year studied
  • But, the bottom line is that there are a huge number of potentially preventable deaths, that the number is probably in the general ballpark of what they report, and that as such a huge issue, we should be devoting large amounts of resources to deal with this (i.e., one might think that prioritizing this issue makes sense, perhaps over developing/using another orphan drug for a rare disease, or devoting large amounts of resources to providing very expensive care to a terminal cancer patient where the benefit is on the order of a few months of additional life or less)
  • One very related issue to me is the remarkably backward nature of our health care system. It seems to me that the primary way to avoid preventable hospital-related deaths is to prevent hospitalization. Which for many of my patients in the 80-100 year old range, means preventing their going to the ER unless really necessary. Which means redesigning the orientation and reimbursement of the health care system to value primary care, move away from the 10-20 minute appointments (which, in the era of electronic medical records, translates to 5-10 minutes actually spent with the patient during which time we take care of their diabetes, hypertension, depression, domestic violence/other social issues, and their preventive care issues, etc.). And giving us the time and associated reimbursement to allow us to really take care of the patients’ problems, be accessible to avoid unnecessary ER visits and thereby decrease unnecessary hospitalizations. My experience is that when one of my frail patients goes to the ER for a likely minor problem, they are usually admitted (and I do not blame the ER physicians, since they see a frail person, do not know them, are not sure they will get outpatient follow-up, and feel that it is better to be safe than sorry. Though I almost never get a phone call to see if we can see the person the next morning. And the reality is that about 50% of my elderly patients admitted do not need admission, they often stay longer than they should, they decondition after 2 days, then they go to a rehab facility to recondition……and, in many cases, they become delirious and are put on unnecessary medications which lead to significant morbidity.
  • Of note, the April 30 issue of Lancet had a brief article and relevant editorial supporting a fundamental reworking of primary care for the NHS in the UK, with a large program to increase primary care recruitment, support primary care, streamline bureaucracy and improve reimbursement (see https://www.england.nhs.uk/ourwork/gpfv/ for a 5 year plan). There is also a report Primary Care by the House of Commons Health Committee “which emphasizes the need for increased funding of general practice to improve access to care and services for patients, such as extending the traditional 10 minute appointment time” — though I was unable to locate that report. And this is in the UK, which already has a universal, reasonably coherent/connected, accessible system of care (i.e., already much beyond us)…

Primary Care Corner with Geoffrey Modest MD: Orthostatic Hypotension Revisited

20 May, 16 | by EBM

By Dr. Geoffrey Modest

I decided to repost a blog from 11/12/14 on initial orthostatic hypotension, with a few additional comments, because I am finding this issue to be so common in my older patients. I am concerned that there is often a combination of pretty common age- and morbidity-related problems, often with some combination of medication adverse effects (some of the most egregious being a- or b-blockers, diuretics, narcotics, vasodilators including calcium-channel blockers or hydralazine), alcohol, morphine, dehydration (esp in the hotter times of the year), autonomic neuropathy (esp from diabetes), and just the plain old decrease in baroreceptor response with aging. And, I am a little concerned about being overaggressive with application of the SPRINT trial results to the elderly (which, of note, excluded diabetics), suggesting benefit for more aggressive BP management in older patients. (See http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/. For a historical review of initial orthostatic hypotension, see Wieling W. Clinical Science 2007; 112: 157.

Here is the blog from 11/12/14:

Circulation had an article on the prevalence of orthostatic hypotension in Ireland (see Finucane C. Circ 2014; 130: 1780). This study involved 4475 community-based people over age 50 from a nationally representative cohort study (TILDA — The Irish Longitudinal Study on Ageing — that’s how they spell “aging”…), recording blood pressure and pulse response to standing. They looked at initial orthostatic hypotension (defined as a BP decrease of >40 mmHg systolic or >20 mmHg diastolic within 15 seconds of standing and associated with symptoms of cerebral hypoperfusion), and typical orthostatic hypotension (defined as a BP decrease of >20 mmHg in systolic or >10 mmHg in systolic after 3 minutes of standing).

Findings:

  • Cohort baseline characteristics: average age 62.8, 51.8% female, 19% smokers, 7.5% diabetes, 34.5% hypertensive, total of <11% with any cardiovascular history — so pretty healthy
  • Initial orthostatic hypotension was found in 32.9% of those >50yo, no difference by age or gender
  • Typical orthostatic hypotension was found in 6.9% overall, increasing from 4.2% in 50 yo to 18.5% in those >80yo
  • Prevalence of failure to return to baseline blood pressure after standing 40 seconds increased with age: from 9.1% in 50 yo to 41.2% in those >80yo

So, a few points (some added since the original blog).

  1. The pathophysiology and epidemiology of initial orthostatic hypotension is somewhat different from the typical orthostatic hypotension. With initial orthostatic hypotension, there is a rapid temporal mismatch between cardiac output (there is an immediate increase in heart rate due to inhibition of vagal activity within seconds of standing, stable stroke volume, and a sharp increase in cardiac output). But the rapid fall in blood pressure after standing (approx 25 mmHg in several studies) is most likely from a marked decrease in vascular resistance (which is around 40% in studies). This typically happens in thin young people (who need to dangle their legs prior to getting out of bed, for example) and those on a-blockers (including reports with tamsulosin for BPH). The typical orthostatic hypotension results from standing, pooling of blood in the legs, decreased venous return, which usually triggers a baroreceptor reflex inducing vasoconstriction (so the usual change is a decrease of about 5 mmHg systolic and a slight increase in diastolic, which rapidly reverses with rapid vasoconstriction). But without this vasoconstriction, there is subsequent decrease in cardiac output and hypotension. This tends to happen in older people who have diminished baroreceptor responsiveness, and in those with hypovolemia, on aggressive diuretics, tricyclic antidepressants, etc.
  2. I don’t want to over interpret this study. The population studied was racially and ethnically pretty uniform. There was no information on whether there was a difference if they had underlying hypertension or what medicationsthey were taking. There are no data on whether the typical orthostatic hypotension was symptomatic. And the limited data available do not all point to asymptomatic hypotension as a cause of falls, for example.
  3. BUT, to me, these numbers are very impressive. I do typically check orthostatics on my elderly patients and very often do find marked hypotension on standing, sometimes symptomatic and sometimes not. When the patient is symptomatic (either by history at home, e.g. when standing, or in the office), I do not hesitate to back off on BP meds (or if they are not on them, I sometimes need to use fludrocortisone or midodrine and suggest high salt diets to raise the blood pressure). In asymptomatic patients, the decision is harder. In general, I am pretty concerned that they may have an even more exaggerated hypotensive orthostatic response if they are a little dehydrated (hot summer day), or don’t drink their usual amounts of fluids, or have GI fluid loss through vomiting/diarrhea, or even postprandially, when blood pressure tends to be lower. So, I use an even less stringent definition than the above: if an elderly patient has a sitting blood pressure with systolics in the 120-140 range which decreases to the 90-100 range even though asymptomatic at the time I am seeing them — I’m just not sure that this fully reflects their condition at home at different times (e.g. hot weather) and I am pretty concerned about falls, as well as potential cognitive decline (see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/ ), or decreased coronary perfusion because of low diastolics.
  4. And my experience does pretty much reflect the data from the Irish study above, where initial orthostatic hypotension happened in 1/3 of the patients over age 50 and may not return to baseline for quite some time
  5. What does this mean in light of the SPRINT trial, where even those >75yo (mean age 80) benefited clinically from lower blood pressures? For me, it means a few things:
  • I need to have a dependable blood pressure reading: the blood pressure recorded by the medical assistants after they have the person walk from the waiting room into the vital signs area is often 30+ mmHg more than I get with a repeat manual reading when the patient has been sitting in my exam room for a few minutes (which may speak to the level of deconditioning of many of my older patients, and even a good number of younger ones…). And I do regularly check orthostatics both right after the person stands and after a few minutes. I also try to get home-based BP recordings, which in some cases is much lower than I find in the clinic (see http://blogs.bmj.com/ebm/2015/01/15/primary-care-corner-with-geoffrey-modest-md-uspstf-recs-on-ambulatory-blood-pressure-monitoring/ for example)
  • And, if an older nondiabetic person can achieve a blood pressure of 120-130/70 range without exaggerated initial or postural hypotension leading either to symptoms or a systolic <100-110 range, I do think that this goal is clinically preferable, per the SPRINT trial.

Primary Care Corner with Geoffrey Modest MD: Fasting Lipids? Not so Fast

19 May, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent review summarizing the data and strongly suggesting that we use nonfasting lipid testing (see Mora S. JAMA Internal Medicine; published online April 27, 2016).

Details for these recommendations:

  • There was a recent consensus statement from the European Atherosclerosis Society comparing nonfasting with fasting lipids, finding that there was not more than an 8 mg/dl difference in total cholesterol, calculated LDL, non-HDL cholesterol, and up to a 26 mg/dl difference for triglycerides, with no difference in HDL, apo A or B (see Nordestgaard BG. Eur Heart J in press with doi:10.1093/eurheartj/ehw152). They go on to suggest we “consider” a fasting sample if the non-fasting triglycerides are >440 mg/dl.
  • Several studies have found pretty consistently that nonfasting lipids are appropriate for general cardiovascular screening, including the impressive large study by Mora from 2008 mentioned in last blog below. Also there was a meta-analysis of 68 studies which found no diminution of the association between lipids and CVD when using nonfasting measurements
  • Studies that have specifically included both fasting and nonfasting lipid determinations have found similar and sometimes stronger cardiovascular disease associations with nonfasting vs fasting determinations (including LDL and triglycerides)
  • Although many intervention studies have used fasting lipids, 3 large clinical trials with 43000 patients used nonfasting lipid determinations
  • Current recommendations are quite mixed: NCEP suggests fasting lipids, USPSTF recommendations are for either fasting or non-fasting cholesterol and HDL (which is the same as the 2015 NICE recommendations). Even the 2013 ACC/AHA cholesterol guidelines, which suggested that initial screening be with fasting lipids, does allow for nonfasting total and HDL cholesterol (in order to calculate the chol/HDL ratio, or the non-HDL levels)

A few comments:

  • I personally have been only using nonfasting lipid measurements for the past 20+ years after I saw a study from the Boston VA hospital which showed very small differences (<10%) between fasting and nonfasting values, with the huge benefit of ordering nonfasting blood work being that I could get the lab test when I was seeing the patient (i.e., the patient did not have to return in a fasting state, the test would get done more reliably, and with diabetics it seemed a mixed message to say that one needs to regularize their eating patterns as much as possible but come in tomorrow am before breakfast to get your blood test…). Since then, there have been a variety of studies confirming the utility and some suggesting the superiority of nonfasting levels.
  • Even the data on triglycerides, which have the most variation with eating, find that nonfasting triglycerides are a better predictor of cardiovascular events than fasting (there were several articles in a single issue of JAMA in 2007 finding this, including Bansal S. JAMA 2007; 298: 309). Perhaps this should not be surprising, since we do seem to eat pretty regularly/perhaps too often and our bodies are more exposed to nonfasting than fasting lipids. And there are even studies showing that the role of triglycerides is even more important in those with larger areas under the curve after eating: given the same meal, some people have more profound and longer lasting increases in triglycerides, which seems to correlate with more clinical disease).
  • Since I have written about this before, I will add a blog from 8/4/14, which also refers to the blog from 11/14/12, and also refers to the study by Samia Mora from 2008, who wrote the article above.

Blog from 8/4/14:

Over the years, I have sent out several blogs on the utility of checking nonfasting cholesterol (see blog appended below). There was a recent article in Circulation assessing the prognostic value of fasting vs nonfasting LDL levels in the Natl Health and Nutrition Survey III (see DOI: 10.1161/CIRCULATIONAHA.114.010001). This study reviewed the cross-sectional NHANES-3 database from 1988-1994 and stratified people by fasting status (fasting = at least 8 hours), followed a mean of 14 years and looked at outcomes, using propensity-matched scoring to adjust the subgroups to make them more apparently equivalent (by choosing the fasting and nonfasting cohorts with similar baseline characteristics).
Results:

  • 4299 pairs of fasting and nonfasting people assessed (62% of the whole group had fasting samples).
  • Primary outcome (all-cause mortality): no difference between groups
  • Secondary outcome (cardiovascular mortality): no difference between groups.
  • For both outcomes (not shockingly) there was an equivalent increase as LDL levels increased.
  • They also looked at fasting vs nonfasting triglycerides (which can vary by 20-30% by fasting status) and similarly found no difference in either of the outcomes by fasting status

So, further evidence that nonfasting lipid samples are fine. See my comments in the blog below. Many of the major therapeutic intervention trials for lipid reduction used fasting lipids (reasons not particularly clear why that was chosen, but just for reference, several studies did not – e.g. Heart Protection Study, Anglo-Scandanavian Cardiac Outcomes Trial).

Blog from 11/14/12:

Recent article (see doi:10.1001/archinternmed.2012.3708) which reinforces legitimacy of checking nonfasting lipids. I stopped checking fasting lipids 15+ years ago, when I saw a small study from the VA hospital in Boston showing that there was only a small difference in total and hdl cholesterol in fasting vs nonfasting, and only a 10% or so difference in calculated LDL (added note: there was another larger study in 2012 confirming a <10% variance — see Sidhu D, Naugler C. Arch of Intern Med 2012; 172: 1707-10).  So, I did it mostly because it was much easier for patients and more likely to actually get done. This new study, which is pretty huge, found essentially the same thing. In brief:

  • All blood tests in Calgary,Canada in a 6-month period in 2011 have had the time since last meal recorded. They looked at 200K pts, 99% outpatient blood tests. Controlled for age and sex.
  • Variance for total cholesterol and HDL was less than 2% (some recommendations suggest only testing chol and HDL, and these are the lipids input into the Framingham model)
  • Variance for calculated LDL was <10%
  • Variance for triglycerides was <20%
  • This article did not look at clinical outcomes

There have been a litany of articles in the past several years, several on triglycerides, showing nonfasting is superior to fasting in prediction of stroke, for example. (Triglycerides vary the most by fasting status, and one of the historic issues is that there is no standardized meal prior to checking non-fasting triglycerides, so how reproducible is it????). But these studies were pretty impressive. One of the physiologic reasons may be that high triglycerides after a meal may reflect decreased clearance associated with hyperinsulinemia/metabolic syndrome. So, either the metabolic syndrome is to blame, or perhaps the increased tissue exposure to high triglycerides and low HDL (they go together here) over time (i.e., increased area under the curve). There are also other articles which look at clinical events in fasting and nonfasting measurements. A large study by Mora at the Brigham have found that nonfasting chol and HDL as well as triglycerides were at least as predictive of events as fasting (see DOI: 10.1161/CIRCULATIONAHA.108.777334). More recently there has been more disparity in the recommendations from different medical societies, with some suggesting fasting and others nonfasting samples, which I think reflects the above list

Primary Care Corner with Geoffrey Modest MD: Dropping Teen Birthrates

18 May, 16 | by EBM

By Dr. Geoffrey Modest

MMWR found a decrease in teen birth rates and prior disparities for those aged 15-19, comparing 2013-14 with 2006-7  (see http://www.cdc.gov/mmwr/volumes/65/wr/mm6516a1.htm?s_cid=mm6516a1_w ).

Findings:

  • From 1991-2014, the overall birth rate among those 15-19 yo declined 61% !!!, from 61.8 to 24.2 births/1000 women, and is currently the lowest ever recorded
  • Nationally, from 2006 – 2014 the teen birthrate decreased 41% overall, comparing 2006-7 and 2013-14:
    • 35% among whites (from 26.7 to 17.3/1000 teens)
    • 51% decrease among Hispanics (from 77.4 to 38.0/1000 teens), with the birth rate ratio vs whites declining from 2.9 to 2.2
    • 44% decrease among blacks (from 61.9 to 34.9/1000 teens), with the birth rate ratio vs whites declining from 2.3 to 2.0
  • By states, all had pretty dramatic decreases, the least in N Dakota at 13.4% and West Virginia at 14.9%, the most in Arizona at 47.8%, Connecticut at 47.6% and Colorado at 47.6%; almost all the other states are in the 30-40% range
  • There was huge variation of teen birth rates by county: from 3.1 to 119.0/1000 females aged 15-19. The highest birth rates being in Texas and much of the south (New Mexico, Oklahoma, Arkansas, Louisiana, Mississippi, Kentucky, Georgia)
  • For the states in the highest quintile of teen birth rates, the mean % of the population >15yo who are unemployed, mean % of population >24yo with an associates degree or higher, and mean family income were 10.5%, 19.9% and $46,005; in the lowest quintile, those numbers were 7.6%, 40.4%, and $73,967 and p<0.001 for all comparisons

So, a few observations:

  • It is certainly welcoming that the racial disparity gap is improving, but it has a long way to go
  • In some states this reflected a cross-ethnic consistency – e.g. in New Jersey: the teen birth rate in 2013-4 among whites was 4.8/1000 (below the national average of 18.0), for blacks was 27.4/1000 and Hispanics 31.3/1000 (also below the national averages of 37.0 and 39.8), though still a pretty staggering 6-7 fold higher than for whites
  • But in others, the disparities diverged: e.g. Nebraska, birth rate for whites was 16.2 (approx the national average) whereas the rates for black and Hispanic (42.6 and 53.9) were far above the national average for these groups.
  • The county-by-county map basically shows the highest teen birth rates are in the South, and largely coincides with those states there that refused to expand Medicaid through Obamacare
  • And, not so surprisingly, high teen birth rates also coincide with those states with the highest poverty rates and (somewhat less impressively, though pretty clearly) with highest numbers of African-Americans and Hispanics (see: map for poverty:  http://www.povertyusa.org/the-state-of-poverty/poverty-map-state/# ; map for racial disparities: https://www.google.com/search?safe=active&espv=2&biw=1280&bih=899&site=imghp&tbm=isch&source=hp&biw=&bih=&q=map+of+ethnicities&oq=ethnicities+map&gs_l=img.1.0.0i8i30.15110.19529.0.22183.19.13.3.3.3.0.151.960.10j2.12.0….0…1ac.1.64.img..1.18.983…0j0i24.p9s7jYX4pj8#safe=active&tbm=isch&q=map+of+ethnicities&chips=q:map+of+ethnicities,g_1:usa&imgrc=WU9o2tjooIVI-M%3A )
  • The US Dept of Health and Human Services has been funding community-wide initiatives in 9 communities with some of the highest teen birth rates, focusing on black and Hispanic teens, with a goal to address the social determinants of health at the community level. Mostly these have focused on access to health care services and pregnancy prevention programs [but, not really looking at the fundamental issues of poverty, unemployment, inadequate education, etc.]
  • As a reference point, the adolescent birth rate is 34.2/1000 females in the US, 25.1 in the UK, 15.5 in Australia, and pretty much under 10 in the rest of Europe (see http://internationalcomparisons.org/intl_comp_files/sheet010.htm )
  • So, to put this together: teen pregnancy is clearly decreasing in the US, with decreasing racial/ethnic disparities, but the US overall has the highest rate as compared to other resource-rich countries, and there are large discrepancies in different regions of the US, largely tracking those areas of poverty, racial disparities, and fewer federal resources (which in some cases are those states have chosen to reject). Again, this really speaks to the need for a national, coherent approach to the inequities in our society, as a basis to improve public health outcomes overall.

Primary Care Corner with Geoffrey Modest MD: COPD – Safety of LABAs

17 May, 16 | by EBM

By Dr. Geoffrey Modest

The recent SUMMIT study assessed the efficacy of combination steroid plus long acting b-agonist (LABA) therapy in patients with COPD, specifically looking at survival in those at high cardiovascular risk (see Vestbo J. Lancet 2016; 387: 1817), finding no increased mortality. A drug company sponsored study.

Details:

  • 16,485 patients 40-80 yo from 1368 centers in 43 countries, with cardiovascular disease (CVD) or at high risk of CVD, and post-bronchodilator FEV1 of 50-70% of predicted. Also at least 10 pack-years of smoking and modified MRC dyspnea scale of at least 2 (patient describing shortness of breath as: “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”
  • Mean age 65, 25% women, 81% white/17% Asian, BMI 28, 47% current smokers, post-bronchodilator predicted FEV1 60% (with 8% reversibility by the bronchodilator), 16% on pre-study anticholinergic, 34% on LABA, and 33% on steroid inhaler, 60% without COPD exacerbation in prior year/25% with one episode, 51% with CAD, 20% PAD, 10% stroke, 17% prior MI, 9% diabetes, 90% hypertension, 66% hyperlipidemia, 56% on antithrombotic, 67% lipid lowering med, 70% RAAS antagonist, 34% b -blocker). So, overall, 71% had established cardiovascular disease or diabetes, and 28% were at high risk. All inhaled steroids or long-acting bronchodilators (which would include anticholinergics) were stopped prior to the study
  • Randomized to: placebo, fluticasone 100 mcg, the LABA vilanterol 25mcg, or the combo. All once a day. Followed 1.8 yrs (max 4 yrs)

Results:

  • Medication adherence was high: 97% were taking >80% of prescribed meds
  • Primary outcome (all-cause mortality): 1037 deaths—not statistically different between groups, but varying from 6.7% on placebo to 6.0% on combo therapy. Mortality overall by diagnosis –Cardiovasc: 3.0% (43% of the total); pulmonary: 0.9% (13% of total); 1.5% cancer (23% of total)
  • Secondary outcome: composite of cardiovascular events (cardiovasc deaths, MI, stroke, unstable angina, TIA): no significant difference
  • Secondary outcome: on-treatment decline in FEV1: combo therapy reduced the decline (38 ml/year, vs 46 ml/yr on placebo, similar results with fluticasone, but no diff between LABA and placebo
  • Very small numbers of COPD exacerbations, but significant differences in annual rates with each active med over placebo [but pretty small absolute differences]:
    • Placebo: 0.35 for moderate and severe, and 0.07 for severe
    • Either single agent LABA or fluticasone: 0.31 and 0.06
    • Combo: 0.25 and 0.05
  • Adverse events. Not different between groups, including pneumonia

So, a few points:

  • I think this is an important study for several reasons:
    • The literature up till now has been pretty mixed on the question of overall or cardiovascular mortality in those with COPD specifically related to LABAs, though no definitive trial had looked at this outcome. The best study so far did find reduced cardiovascular and pulmonary mortality on a secondary analysis: the TORCH study (Calverly PM. NEJM 2007; 356: 775) assessed fluticasone 500mcg plus salmeterol 50 mcg twice daily (an 8-fold higher dose of steroid than in SUMMIT) and in patients with moderate to severe COPD but lower cardiovascular risk, finding an almost significant decrease in mortality (15.2% in placebo, 12.6% with combo therapy, an 18% decrease but p=0.052).
    • And, this CVD outcome is really important: not only do COPD and CVD have shared risk factors (e.g., smoking, air pollution, systemic inflammation, endothelial dysfunction, sedentary lifestyle), but those with moderate symptomatic COPD are more likely to die from CVD than any other cause (and in the SUMMIT study, 43% of deaths were attributed to CVD)
  • A few caveats:
    • Most of these patients in SUMMIT were pretty stable (e.g. COPD GOLD B), with only 15% having had a history of 2 or more exacerbations in the prior year
    • The study unfortunately did not allow baseline use of anticholinergics (e.g. tiotropium), which is the first line drug in COPD I have been using, given the prior mixed reviews on cardiac mortality with LABAs. [Though the 2013 GOLD recommendations do give equal weight to anticholinergic or LABA as first line (see Vestbo J. Am J Respir Crit Care Med 2013; 347)]
    • Though the combo steroid/LABA did increase statistically the FEV1 (and was clearly better than placebo), the difference was not clinically significant (only 8 ml/yr). On reviewing the decline of FEV1 over 3 years, the curves were really parallel (averaging a decline of about 40 ml) in all groups, suggesting that longer follow-up would be unlikely to further improve FEV1 In fact, the only real difference in the curves was that at the 90-day mark, where they based the initial assessment of FEV1 decline, there was an increase of around 40 ml in those with active treatment, so the measured decline was really based on an increase in the initial set-point, especially in the curves of patients on fluticasone.
    • It is difficult to compare the SUMMIT and TORCH trials, since in the latter, the patients had more severe COPD, were at lower CVD risk, but had much higher steroid dosing. The higher trend to increased survival in those in the TORCH study vs the SUMMIT study may well have been from the increased fluticasone dosing or other characteristics of the patient population. Perhaps the close-to-significant mortality benefit found in TORCH (which was equally spread through cardiovascular and pulmonary causes) would have been significant in a larger study such as SUMMIT, especially if the TORCH patients had higher CVD risk. But there was the likely trade-off of increased pneumonia rate/year in TORCH (0.07 vs 0.039 in SUMMIT) likely related to the higher steroid dose.
  • So, bottom line, SUMMIT was not a perfect study for COPD (since they did not use baseline tiotropium, and it was a very stable COPD  group with very few exacerbations). But it was very impressive that in this group with high cardiovascular risk, the combination of an inhaled steroid and LAB, or either individually, was not associated with increased mortality and specifically cardiovascular events (though, importantly, patients had moderately reasonable baseline CVD preventive meds). It was reassuring in this large study that there was no increase in pneumonia associated with the steroids, though they used a much lower dose than is often prescribed (100 mcg fluticasone). But the SUMMIT study does give more definitive and stronger support to using either LABA or anticholinergic as the first-line agent.

Primary Care Corner with Geoffrey Modest MD: Use of Statins in Patients with Hepatitis? Looks Like a “Yes”

16 May, 16 | by EBM

By Dr. Geoffrey Modest

One question that comes up a lot in patient care is whether it is safe to use statins in patients with ongoing hepatic inflammation. A new retrospective VA study of hepatitis C (HCV) patients found an actual benefit for statins, as has been found in some other studies (see DOI 10.1002/hep.28506).

Details:

  • From the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, they looked at subjects initiated on anti-HCV therapy from 2001 to 2014, as well as all incident cases of cirrhosis and hepatocellular carcinoma (HCC). Those coinfected with HIV or hepatitis B were excluded, as well as those with baseline cirrhosis
  • Mean age 53, 65% white/18% black/6% Hispanic, 95% male, ALT 75, AST 53, FIB-4 score 1.7 (see below), median length of follow-up was 7-8 years. More statin users were diabetic (24% vs 9%), on metformin, other lipid-lowering agents, ACE-I, and they had a higher baseline LDL , triglycerides, and lower HDL). 90% were treated with PEG/RBV, 10% with PEG/RBV/telaprevir (i.e., the old drugs)
  • 9135 eligible people, of whom 1,649 developed cirrhosis, and 239 developed incident HCC [cirrhosis was defined by a FIB-4 score of >3.5, where the FIB-4 score is a mathematical calculation based on age, AST, platelet count, ALT]

Results:

  • Statin use was associated with
    • Higher likelihood of sustained viral response (55.1% vs 47.5%, p<0.0001)
    • A 36% reduction in development of cirrhosis, adjusted HR: 0.64 (0.53-0.68), p<0.0001.
    • Lower fibrosis progression, with a dose-response curve revealing progressively decreasing risk
  • Of the statins used, the highest decrease in FIB-4 score was with atorvastatin and fluvastatin (though only 34 patients were on fluvastatin): those without statin had FIB-4 increase of 0.26, those on simvastatin had increase of 0.11, but those on atorvastatin had decrease (-0.17), p=0.04,after adjustment for baseline FIB-4 score and established predictors of cirrhosis.
  • Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed. [Interestingly, the decrease in HCC was independent of changes in the FIB-4 score. Though with hep C, the progression to HCC is tied in with presence of fibrosis].

So, does this make sense?

  • There are several mechanisms by which statins could decrease progression of liver fibrosis:
    • They have lots of “pleiotrophic” (non-lipid) effects: anti-inflammatory, antiproliferative, anitangiogenic, pro-apoptotic, immunomodulatory. And there are data suggesting they can inhibit cell growth, decrease proteolysis, block tumor spread, and may be chemoprotective against such malignancies as HCC.
    • Hepatitis C virus depends on cholesterol to replicate, so interference by statins might well help control hep C (statins do inhibit hep C in vitro; and people with hep C have lower LDL levels, which increase after the virus is cleared)
    • Statins also decrease components of the metabolic syndrome, and there are several studies suggesting that the combination of hep C infection and metabolic syndrome, present in about 20-25% of people with hep C, leads to a higher incidence of HCC
    • Humans studies (including another one from the above VA database: Butt AA. Hepatology 2015; 62: 365) have found decreased risk of hepatic fibrosis progression and development of cirrhosis by 43%; a Taiwanese study found that just using statins in patient with hep C infection found a reduced risk of cirrhosis in a dose-dependent fashion, also found in the HALT-C study. Another VA study of patients with compensated cirrhosis found a 45% decreased risk of decompensation and a similar mortality benefit
  • For patients currently on DAAs (direct-acting antiretrovirals) for hepatitis C, I found the following drug-drug interactions:
    • Ledipasvir/sofosbuvir possibly increases the levels of the statins (I checked atorvastatin, pravastatin, rosuvastatin, and simvastatin), though the warning for atorvastatin seems the most benign
    • Elbasvir/grazoprevir increases atorvastatin dose by 94%, rosuvastatin by 126%, simvastatin has likely interaction but not studied, no interaction with pravastatin
    • Daclatasvir expected increases in levels of atorvastatin, pravastatin, simvastatin — not studied, and 58% increase in rosuvastatin
    • Ombitasvir/paritaprevir/ritonavir increases levels of rosuvastatin 1-2 fold and pravastatin by about 33%. do not use with atorvastatin or simvastatin
    • And, none of the statins seemed to affect the levels of the DAAs

Effects of statins on other hepatitides:

  • NAFLD: statins have been shown also to decrease liver inflammation in those with NAFLD
  • One of my favorite studies, because of its name, was the GREASE study, which in fact was a study of Greek people with high lipids!! (Athyros VG. Lancet 2010; 376: 1916). They looked at 437 patients with baseline elevated ALT (but < 3x the upper limit of normal), 90% with metabolic syndrome, and all with LDL>100 and documented CAD, finding that atorvastatin for 3 years led to 1/3 the rate of recurrent CAD events (30% in placebo and 10% with atorvastatin), but 89% had normalization of their LFTs on the statin (although a simultaneous increase in ALT in those on placebo)
  • Hepatitis B: data on hepatitis B is somewhat mixed:
    • There are case reports of asymptomatic hepatitis B reactivation in a patient on atorvastatin, which resolved with discontinuation of the atorvastatin (see Wu DC. Intl J Infect Dis; 2013:e1069). Though, I should add that I had a patient with chronic hepatitis B, who was asymptomatic but developed a dramatic increase in his ALT to 450 on routine check after being on atorvastatin for 8 years, and the hepatic inflammation spontaneously resolved within weeks even while continuing the atorvastatin. So, it seems that even if statins did cause the hep B reactivation, there are not necessarily bad outcomes (perhaps my patient had HBV reactivation related to the statin, but then enough of an immunologic response to contain it).
    • On the other hand, a recent 2-year Chinese study (Hsiang JC. J Hepatol 2015; 63: 1190) in patients with chronic HBV infection found a 32% decreased risk of HCC in those on statins, and on subgroup analysis, those on a statin and nucleos(t)ide analog had a 59% risk reduction compared to those on a nucleos(t)ide analog alone (i.e., the combo might even be better: which may be really significant for HBV, since unlike hep c, the development of HCC is not so dependent on having baseline cirrhosis)
    • In general, it is pretty well accepted that there is no significant relationship between statin use and liver disease. In most large trials, there is no increase in statin-induced liver disease. As a result, the FDA changed their recommendations in 2012: check LFTs prior to starting statins, then only if clinically indicated

So, what does this all mean in the era of the potent new hepatitis C drugs?

  • My guess is that it is very unlikely that a statin will improved the efficacy of these new hep C drugs, since they are so powerful on their own
  • The issue of statin effect on decreasing the progression of fibrosis/cirrhosis is interesting, as well as the decreased likelihood of developing HCC. Unclear exactly why: it may well be that the effect of statins is not a direct effect on the development of these conditions, but simply its anti-inflammatory effect (though that is still welcome, and still could have long-term effects in preventing cirrhosis). And this could also be different in the current era of hep C treatment
  • If someone is on a statin prior to starting hep C DAA therapy, it makes sense to check the most up to date drug interactions (e.g. at http://www.hep-druginteractions.org/checker ) and likely decrease the dose of the statin, stop or change the statin, as indicated
  • For someone with hepatitis C who is not currently on treatment, it looks to me like there are good reasons to use a statin, probably best for atorvastatin (in part for its role in preventing CAD in those with this chronic inflammatory state — though it would be important to have confirmatory RCTs; and in part based on the above studies of its anti-hep C potential)
  • And, overall, it seems very likely than statins may be useful for those more generally with inflammatory liver disease, with reasonably impressive data for NAFLD and probably as well for hepatitis B. It would be really great to have more long-term data, preferably based on RCTs, which looked at real clinical outcomes and not just changes in ALT as with the NAFLD data (though I should add that the dramatic decrease in CAD events seems to justify the use of statins independent of their hepatic effects. And there are some data suggesting that simvastatin is less effective in decreasing biopsy-proved hepatic inflammation than atorvastatin). So, I have been using atorvastatin in particular in my patients with NAFLD and both hepatitis B and C, but following their LFTs more regularly, even in asymptomatic patients.

Primary Care Corner with Geoffrey Modest MD: Warfarin in Nonvalvular Atrial Fibrillation

13 May, 16 | by EBM

By Dr. Geoffrey Modest

Over the years, I have sent out several blogs about the drug company shenanigans/malfeasance in studies promoting NOACs (non-vitamin K antagonist oral anticoagulants) — See link at bottom. Here is a large study suggesting the benefits of warfarin (See doi:10.1001/jamacardio.2016.0199 ). The authors note that studies finding NOAC superiority were in comparison to warfarin where the times-in-therapeutic range (TTR) varied from 55.2% to 64.9%. In the current study researchers looked at the relative effectiveness of warfarin for patients with atrial fibrillation (AF) as it varied with TTR. Data are from a large Swedish registry.

Details:

  • Retrospective, multicenter cohort study of 40,449 patients
  • 40% women, mean age 73, mean CHA2DS2-VASc (see below) score 3.3, TTR<70% in 43%, hypertension 60%, heart failure 30%, renal failure 4%, excessive alcohol use 2%, history of falls 8%, prior major bleed 6%, MI 21%, diabetes 18%, stroke 19%, TIA 8%
  • 4311 patients also on aspirin with the warfarin, with the concomitant diseases/risk factors about the same as the overall cohort except that 43% had a prior MI (vs 17% just on warfarin)

Results:

  • Annual all-cause mortality 2.19% (2.07-2.31), intracranial bleed 0.44% (0.39-0.49)
  • Comparing those with TTR <70% vs >70% (all are annual rates)
    • All-cause mortality was 4.35% vs 1.29%
    • Any major bleed was 3.81 vs 1.61%, with intracranial bleed 0.72 vs 0.34%; GI bleed 1.26 vs 0.56%
    • Any thromboembolism was 4.41 vs 2.37%, MI 1.90 vs 0.98%, venous thromboembolism (VTE) 0.24 vs 0.09%, and arterial embolism 2.52 vs 1.41% [thromboembolism defined as: stroke, TIA, peripheral arterial emboli, venous thromboembolism, MI]
  • The role of INR variability (dividing those around the median of higher vs lower variability in their cohort): comparing high vs low
    • All-cause mortality was 2.94% vs 1.50%
    • Any major bleed was 3.04 vs 1.47%, with intracranial bleed 0.51 vs 0.38%; GI bleed 1.05 vs 0.50%
    • Any thromboembolism was 3.48 vs 2.46%, with MI 1.53 vs 0.96%, VTE 0.16 vs 0.11%, and arterial embolism 1.98 vs 1.51%
  • For those with TTR >70%, INR variability did not matter
  • For those on aspirin
    • All-cause mortality was 2.57% vs 2.13%
    • Any major bleed was 3.07 vs 2.04%, with intracranial bleed 0.62 vs 0.41%; GI bleed 1.16 vs 0.67%
    • Any thromboembolism was 4.90 vs 2.12%, with MI 1.53 vs 0.96%, VTE 0.19 vs 0.12%, and arterial embolism 2.72 vs 1.54%
  • For those with renal failure, intracranial bleed more than twice as common, with HR 2.25 (1.32-3.82)
  • The strongest predictor of intracranial bleeding was renal failure

So, a few issues:

  • These data, though not from a prospective, randomized study, do reflect more of a real-world community setting.
  • The results for patients in good control (TTR>70%) is actually better than in the “pivotal NOAC studies”.
  • In terms of the issue of using the combo of warfarin and aspirin:
    • I am very concerned about the increased serious adverse events with this combination (see http://blogs.bmj.com/ebm/2014/11/20/primary-care-corner-with-geoffrey-modest-md-aspirin-plus-warfarin-for-afib-and-cad/ , which looks at several observational studies on aspirin plus warfarin for patients with AF and CAD, all showing much higher risks (e.g., bleeding) without any clear benefit. The PREFER trial (see De Caterina, R. Heart 2014; 100: 1625) looked at a large European registry of patients with AF and found that 95% of those on dual antiplatelet and anticoagulation therapy did NOT have an “accepted indication” (i.e.: acute coronary syndrome or stenting –and, this is the current recommendation of the European Society of Cardiology guidelines in AF: anticoagulant therapy only except in these indications).
    • In the above Swedish study, only 2.6% of those on additional aspirin had a clear indication for this therapy. And this study really supported NOT using aspirin, given the higher mortality, higher MI/VTE/arterial embolism, and much higher bleeding risk (though, as noted, this was not an RCT, had many more patients with prior MI, so it is not so surprising that there was an increase in these thrombotic events. But twice the level of major bleeds???  And 50% more thrombotic events??? Is aspirin really useful?? I personally have stopped aspirin in my patients on warfarin, based on the prior blog)
  • So, my bottom line: this Swedish study confirms the utility of warfarin in patients with nonvalvular AF, though clearly differentiates its advantages in those in good control (INR in range >70% of the time) vs not. I do have trouble with the NOACs overall, given the noted drug company issues in my prior blogs and the lingering concern that if they are in an accident, reversal agents are not widely available. But I have occasionally used NOACs in patients who are leaving the country and cannot get their INR checked, or it is just too difficult to get the INR in range despite best efforts all around, often including home-based nursing care/checking the INR at home. That being said, the clear majority of my patients on warfarin are definitely in the >70% TTR category and seem to be doing just fine…. (though I do need to monitor them frequently, but, then again, most of them have significant cardiac and other morbidities, and my guess is that the increased monitoring/health system contact is actually a positive thing)

CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female])

For older blogs, see: http://blogs.bmj.com/ebm/2016/01/19/primary-care-corner-with-geoffrey-modest-md-antithrombotic-therapy-guidelines/ goes through the antithrombotic therapy guidelines but also reviews the history of drug company malfeasance with the NOACs, which really make me uneasy about using them…

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