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Archive for November, 2016

Primary Care Corner with Geoffrey Modest MD: Optimal blood pressure in patients with atrial fibrillation

30 Nov, 16 | by EBM

By Dr. Geoffrey Modest

It is unclear from the literature what the goal blood pressure should be in patients with atrial fibrillation, and this is not addressed by any of the guidelines. A post hoc analysis of the AFFIRM trial (Atrial Fibrillation Follow-up Investigation of Rhythm Management, a prospective trial assessing the strategy of rate versus rhythm control) looked retroactively at the relationship of achieved blood pressure and outcomes (see Badheka AO. Am J Cardiol 2014; 114: 727)).

Details:

  • 3947 patients in the trial were followed 6 years, noting their systolic and diastolic blood pressures (recorded after sitting quietly for at least five minutes) at baseline and at follow-up, divided into 10-mm Hg increments. The follow-up blood pressure was defined as the average of all available blood pressure measurements during each post-baseline visit
  • Mean age 69, and the following were significantly (and much) more frequent in patients who had lower blood pressure, with average percentages overall as follows:  60% in men, 70% hypertension, 40% coronary artery disease, 25% in patients with heart failure, 14% smoking
  • The endpoints assessed were all-cause mortality; the combination of all-cause mortality, ventricular tachycardia or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, MI, and PE as a composite secondary outcome.

Results:

  • All-cause mortality was observed in 614 people (15.6% of the group)
  • The incidence of all-cause mortality was lowest in those with BP 140/78 mm Hg, with a U-shaped curve. All-cause mortality was:
    • 9 fold higher in the group with systolic blood pressure <110; 1.9 fold higher in those with systolic greater >160
    • 3.9 fold higher in the group with diastolic <60; 1.8 fold higher in the group with diastolic >90
  • There was a similar U-shaped relationship to the composite secondary outcome.
  • Subgroup analyses also found a similar U-shaped curve with an increased all-cause mortality with blood pressure <110/60, including the following subgroups: whether or not they had CAD, hypertension, heart failure, or reduced ejection fraction.

Commentary:

  • One of the complicating factors in assessing the optimal blood pressure in patients with atrial fibrillation is that several of the drugs we use to control rate (e.g. beta-blockers and non-dihydropyiridine calcium channel blockers) also decrease blood pressure. So, one of the complicating factors in interpreting the association between lower blood pressure and increased mortality is inherent in this retrospective observational study: are those who require more medications to control their heart rate at a higher risk of death, just because their harder-to-manage atrial fibrillation is associated with higher mortality? And their higher incidence of hypotension merely reflects their need for more meds (which also lower their blood pressure) to control that rate???
  • Another large issue is the dramatic baseline comorbidities in those with lower blood pressure, reinforcing the fact that these were much sicker patients and raising questions as to whether the study could mathematically adjust for these covariates in their final analysis. The authors did control for age, history of hypertension, history of heart failure, history of MI or revascularization, history of stroke, diabetes, smoking status, use of warfarin, lipid-lowering therapy, diuretics, and which group they were randomized to in the AFFIRM  trial. However, given how apparently sick these patients with low blood pressure were, one wonders if there were other important variables not included (e.g. other medical conditions such as renal failure, or COPD –esp since those with lower BP also had lower BMI, or psychosocial conditions associated with higher mortality such as depression)???
  • And what really is the actual blood pressure in patients with atrial fibrillation? The automated blood pressure cuffs typically use an oscillometric methodology. Studies have shown that many of these cuffs are inaccurate in patients with atrial fibrillation (see DOI: 10.1111/jch.12545). And, a larger issue to me is that there is a large blood pressure variability between measurements in patients with atrial fibrillation, with one measurement picking up a particularly strong, forceful beat, leading to a systolic blood pressure that may be 30 to 40 mm Hg higher than other readings. Some people suggest averaging several recordings (??how many), but I have no idea whether this correlates with clinical events are not, what the best methodology for determining that clinically-relevant BP really should be, or what would be the optimal goal BP (which also requires a good clinical prospective study using a validated methodology. perhaps 24-hour ambulatory blood pressure monitoring with an approved and accurate automated cuff???). As mentioned, i have seen no guidelines address the blood pressure issue: either its measurement or management goals.
  • One issue that is found frequently in observational studies on hypertension is a J-shaped or U-shaped curve. Of note this tends not to be found in controlled trials (e.g. the SPRINT trial), suggesting that there may be a bias in the uncontrolled trials: those with lower blood pressure have higher mortality related to the fact that they have underlying diseases leading to both a lower blood pressure and higher mortality
  • Of note, there are some data suggesting that we do not need to be overly aggressive in controlling rate (see Van Gelder IC. N Engl J Med 2010; 362: 1363), which also raises the interesting question of whether those with aggressive rate control may have had increased mortality because their blood pressure was lower, balancing perhaps a clinical benefit of the lower rate (i.e. there might be some benefit for tighter rate control, but only in those who could achieve this without lowering their blood pressure too much). Unfortunately in this Van Gelder article they did not mention the achieved blood pressures in the 2 groups.
  • This AFFIRM article suggests that the target blood pressure in those with atrial fibrillation may be higher than in the general population. However, the methodologic issues above, to me, simply amplify the issue that there really are no good clinical data guiding us on either how to measure blood pressure or what the goal should be in those with atrial fibrillation….

Primary Care Corner with Geoffrey Modest MD: More Data Supporting Treat-to-Target

29 Nov, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at the relationship between achieved LDL cholesterol levels and changes in coronary artery atherosclerosis progression, as determined by coronary CT angiography, CTA (see doi.org/10.1016/j.jcmg.2016.04.013).

Details:

  • 147 patients with evident atherosclerotic plaques on CTA had quantitative plaque size measured both at baseline and at follow-up CTA two years later (median 3.2 years)
  • Baseline characteristics: mean age 62, 57% male, 65% with hypertension, 33% diabetes, 20% active smoking, 27% dyslipidemia (defined as total cholesterol >240 mg/dL, LDL >130, HDL <40, triglycerides >150, and/or treatment with lipid-lowering agents), cardiac risk score by both the ATP III and Framingham risks:60% low risk (<10% over 10 years), 30% intermediate (10 to 20%), and 10% high risk (>20%). Number risk factors = 1.6
  • Multi-center, observational study, assessing those who had LDL <70, versus >70, to assess changes in quantitative measurement of plaque volume, usingthe modified 17-segment American Heart Association model for coronary segment classification
  • This was an industry-supported study done in 4 Korean  centers

Results:

  • Of note, those that had a follow-up LDL <70 had a higher prevalence of diabetes (p=0.002) [i.e., were likely at even higher risk of progressive disease]
  • Those with an LDL <70 had significant attenuation in plaque progression: 12.7 mm³ versus 44.2 mm³, p=0.014.
  • Multivariate analysis found that the only factor influencing plaque progression was the follow-up LDL level (p=0.021), controlling for age, hypertension, active smoking, and follow-up LDL <70.
  • All patients who achieved an LDL <70 were on a statin (n=37), whereas 63% (n= 70) of those with follow-up LDL >70 were on a statin; those actually taking a statin had similar plaque progression as the overall group, with plaque progression of 12.7 versus 41.8 mm³
  • Subgroup analysis showed that annual plaque volume could be attenuated with aggressive LDL control (4.6 mm³ versus 14.5 mm³)

Commentary:

  • Coronary atherosclerosis remains a major cause of global morbidity and mortality (though decreasing in many resource-rich countries, but increasing in resource poor countries), with an estimated global burden of 17 million deaths annually.
  • Prior studies looking at intravascular ultrasound (IVUS) have shown that intensive LDL lowering can halt the progression of atherosclerosis and even promote some regression. CTA provides a noninvasive assessment of CAD with high reproducibility and a diagnostic performance correlating well with that of the invasive IVUS.
  • As noted by the editorialists (see doi:10.1016/j.jcmg.2016.08.002), several coronary angiography and IVUS studies have found that LDL levels need to be brought down to the 70-80 mm/dL range in order to decrease plaque progression, and even lower LDLs were needed for plaque volume reduction. The above study found almost a 70% decrease in the annual rate of plaque progression in those with LDL <70.
  • Plaque progression is in fact a reasonable surrogate marker for future cardiac events. One study found that plaque progression over time was associated with a 28% likelihood of a cardiac event versus 10% in those without plaque progression. Other studies have shown that plaques with rapid progression were much more likely to be the culprit lesions in cardiac events (i.e., the lesions that rupture and cause an acute cardiac event)
  • A few additional comments:
    • This was not an intervention study. As with other studies looking at achieved LDL and cardiac events, these patients were not randomized to specific LDL targets, so one cannot definitively conclude that it is beneficial to treat-to-target. For example, perhaps those who more easily achieve a lower LDL target have a less malignant atherosclerotic course. However, there are a few lines of argument which suggest that treating to lower LDL targets is highly likely to be beneficial:
      • The Treating to New Targets trial (Barter P. N Engl J Med 2007; 357:1301-1310), which compared the effects of atorvastatin 10 versus atorvastatin 80 mg, found that though the number of clinical cardiac events was lower overall in the group on 80 mg, there was no difference between the two groups if one looked at achieved LDL levels (by the way, this trial also showed that the number of cardiac events was also related to the HDL level: those with LDL >100 but HDL >55 had the same 5-year risk of a cardiovascular event as those with achieved LDL<70, but HDL <38. and statins had essentially no effect on HDL, independent of their dose). see first graph below
      • Data from the constellation of many lipid trials, looking at both the achieved LDL on statins and the natural LDL of patients, show a straight line relationship: those with lower achieved or natural LDL down to 70 had fewer cardiac events. See second graph below. This also suggests, as seen in several studies, that it is the on-statin achieved LDL that matters, and the “pleotrophic” non-lipid effects don’t seem to matter so much.
      • The editorialists had a very similar graph to the second one below (see reference above), showing that achieved LDL targets were associated both with changes in percent of atheroma volume as well as angiographic mean luminal diameter/extent of stenosis
      • The data from the ezetimibe trial (see http://blogs.bmj.com/ebm/2015/06/23/primary-care-corner-with-geoffrey-modest-md-improve-it-trial-ezetimibe/ ) showed that adding ezetimibe to simvastatin decreased cardiac events, more so than simvastatin itself, again suggesting further decreases in LDL were beneficial. The data on PCSK9 inhibitors is more preliminary, but have shown a dramatic decrease in LDL over just using statins, and a decreased cardiac event rate (Robinson JG. N Engl J Med 2015; 372: 1489 studied high-risk patients on max dose statin but LDL >70, then randomized to PCSK9 inhibitor plus statin vs continued statin, and found a 62% further decrease in LDL by the PCSK9 inhibitor and a 48% decrease in cardiac events over 78 weeks). These studies further support a low LDL target
    • So, despite the lack of rock-solid studies, there is a remarkable convergence of data from different types of studies suggesting that targeting a lower LDL is the appropriate approach. The graph in the editorialists’ article shows that the achieved LDL correlates very well with changes in atheroma volume as well as the residual luminal diameter of coronary arteries. The second graph below that shows that clinical events track with the achieved LDL. And the Targeting New Targets trial showed that it was the achieved LDL and not the dosage of atorvastatin (10 vs 80mg, which correspond to “moderate” and “high” intensity statins by the 2013 ACC guidelines) that was associated with clinical outcomes (though the lower achieved LDL was more common with the 80 mg dosage)
  • So why did the new AHA guidelines in 2013 make a point of eliminating the treating-to-target approach? They state that this was because there was not enough rigorous data to show that treating-to-target really mattered (as noted above: no specific trials looked at this). However, many of their other recommendations had much less data to support them, including looking at the individual’s 30-year risk profile or treating a 21 year-old with LDL >190 aggressively (both of which I support, it is just that there really are no data to support these by RCTs, as opposed to the above data which i think pretty strongly support a targeted LDL). My best guess is that they feel that statins are used insufficiently overall, so they wanted to develop the easiest algorithm to reinforce using statins in people at increased cardiovascular risk (in fact, in the above Korean study only 56% of really high-risk patients who were not on a statin initially were actually put on a statin by their clinicians). But there are several studies showing that applying the 2013 recommendations would lead to dramatic overtreatment (eg, the AHA/ACC 2013 guidelines would recommend statins for nearly all men and two thirds of women >55 years old). In addition to exposing lots of people probably unnecessarily to statins, the approach of stratifying patients into needing either intensive- vs moderate-dose statin therapy does potentially create unfortunate clinical consequences in those who clearly need statins:
    • I have seen several patients with clinical CAD who, when put on atorvastatin 10 mg, achieve an LDL in the 40s. Should I really be putting them on high intensity statin? There are more adverse events taking higher dose statins, and what is likely to be the benefit?? (and there are animal data, and old human data on lipid-lowering therapies, as well as the recent PCSK9 studies, finding that there may be neurocognitive issues with too-low an LDL…. Cholesterol is part of the cell membranes of neurons, which is integral to neural transmission)
    • I have also seen many very high-risk patients on atorvastatin 80 mg who do not achieve an acceptable LDL level (specifically, <70). In many cases, by switching them to rosuvastatin 40 mg they have done much better. I have not seen this as a tested clinical strategy, but given our understanding of statins and the above data on the benefit of LDL <70, I think this is a reasonable strategy. And I would try this before adding ezetimibe, or PCSK9 inhibitors…
  • So, I am concerned about the clinical implications of adopting a simple algorithm of “high” vs “moderate” intensity statins: we may be overtreating some patients, as well as undertreating others, in a disease with potentially very bad outcomes and with tried-and-true meds which are quite effective in lowering the likelihood of these events, and with minimal adverse effects. I do in general support an aggressive approach to LDL management, especially in those at higher risk of clinical cardiac events, and I strongly suspect that the clinical risk of undertreating with statins is much higher than that of overtreating. However, I also think we should be tracking and following lipid levels, both to make sure that the patients are taking their statins appropriately, and also to titrate the statin dose to the individual.

ice-cream

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For prior critiques of the 2013 ACC/AHA guidelines, see http://blogs.bmj.com/ebm/2014/05/09/primary-care-corner-with-geoffrey-modest-md-aha-lipid-guidelines-again/ , http://blogs.bmj.com/ebm/2015/01/23/primary-care-corner-with-geoffrey-modest-md-yet-another-analysis-that-lipid-treatment-by-new-guidelines-overdoes-it/ and,  http://blogs.bmj.com/ebm/2015/08/05/primary-care-corner-with-geoffrey-modest-md-comparison-of-the-2013-accaha-lipid-guidelines-to-atpiii/

Primary Care Corner with Geoffrey Modest MD: 2-dose HPV vaccine for girls and boys

28 Nov, 16 | by EBM

By Dr. Geoffrey Modest

On 10/19/16, the CDC recommended that 9 to 14 year olds receive only 2 doses of the 9-valent HPV vaccine at least 6 months apart, instead of the prior recommendation for 3 doses. But those who started the series between ages of 15 through 26 continue to need 3 shots (see http://www.cdc.gov/media/releases/2016/p1020-hpv-shots.html for the press release). Here is the article it was based on (see doi:10.1001/jama.2016.17615).

Details:

  • Open-label, non-inferiority study done in 52 ambulatory sites in 15 countries, with 5 cohorts:
    • Girls aged 9 to 14, getting 2 doses 6 months apart (n= 301)
    • Boys aged 9 to 14, getting 2 doses 6 months apart (n= 301)
    • Girls and boys aged 9 to 14 getting 2 doses 12 months apart (n= 301)
    • Girls age 9 to 14 getting 3 doses over 6 months, the current recommendation (n= 301)
    • Adolescent girls and young woman aged 16 to 26 getting 3 doses over 6 months, acting as the control group (n= 314)
  • Mean age 11, BMI 20, 60% white/17% Asian/10% black, 25% North America/20% Asian Pacific/30% Europe/15% Latin America/8% Africa
  • Eligible 9-14 yo’s had to be generally healthy and not sexually active prior to enrollment. Those in the control group (age 16-26) had to be generally healthy with 4 or fewer lifetime sexual partners. All of the intervention groups were seronegative for each subtype prior to the 1st dose of vaccination
  • The primary endpoint was the antibody response to each of the HPV types, assessed one month after the last dose of vaccine

Results:

  • More than 90% of participants in each cohort seroconverted to each HPV subtype
  • HPV antibody responses in girls and boys given the 2 doses were not inferior to the control group (p < 0.001 for each HPV type).
  • There was essentially no difference between boys’ and girls’ responses to the vaccine
  • There was also no difference between those receiving the 2nd dose after 6 months or after 12 months, though the antibody responses in those receiving the 2nddose after 12 months were someone higher than after 6 months
  • The antibody responses were roughly 2 to 3 times higher in the younger cohorts than the older control for each HPV type
  • Post hoc analysis assessing antibody response 6 months after the last dose of vaccine declined in all of the cohorts, but the antibody responses remained non-inferior in the 2-dose regimens
  • 22 participants had a serious adverse event, all not considered to be related to the vaccine. One person discontinued the study because of transient urticaria

Commentary:

  • The 9-valent HPV vaccine provides protection against 7 high-risk HPV types responsible for 90% of cervical cancers or other anogenital cancers, as well as 2 other types responsible for 90% of genital warts.
  • The WHO in 2014 changed their recommendations for girls aged 9 to 14 from a 3 dose to a 2 dose schedule (at 0 and 6 months).
  • Other studies have suggested that a longer interval between the 1st and 2nd dose is more immunogenic, and that a 2nd dose earlier than 5 months after the 1st dose seems to be less effective; i.e. the second dose should not be before 6 months, and is more immunogenic at least in the short-term if given after 12 months as in the above study, or perhaps even later (the CDC press release only states that the second dose should be at least 6 months later)
  • Other studies of also found that coadministration of the 9-valent HPV vaccine with diphtheria, tetanus, pertussis, polio, and meningococcal vaccines can be done at the same visit.
  • This study did not have clear clinical outcomes, though it seems to me that antibody response is a reasonable surrogate marker for clinical protection. A prior blog (see http://blogs.bmj.com/ebm/2015/04/01/primary-care-corner-with-geoffrey-modest-md-hpv-vaccine-recommendation-update/ , or see Joura EA. N Engl J Med 2015; 372: 711) dealt with the initial recommendations for the 9-valent vaccine, showing that not only was this vaccine immunogenic, it was also quite safe, and provided 7% efficacy in preventing >= CIN2 lesions. — And HPV vaccine is not only quite expensive, it is also very painful and requires more medical visits to do 3 vs 2 injections.
  • It should be noted that there are no data showing what the minimum clinically-effective protective titer is for HPV vaccination
  • The investigators will be following antibody persistence and the duration of protection over time.
  • This study was designed to look at a younger cohort because of their increased HPV-vaccine immunogenicity, as documented in other studies (and confirmed in this study). It certainly seems reasonable that a subsequent study should look at the effectiveness of 2-dose regimens for those older than 14 and those who have been more sexually active/have evidence of prior infection by some of the HPV types.

Primary Care Corner with Geoffrey Modest MD: Reduced Antibiotic Susceptibility of Meningococcus and Pseudomonas

22 Nov, 16 | by EBM

By Dr. Geoffrey Modest

Two recent articles highlight increasing antibiotic resistance.

  1. Neisseria Meningitides
  • Meningococcus is becoming increasingly resistant to third-generation cephalosporins (see or doi:10.1093/jac/dkw400). Details:
    • There are approx 500 cases annually of invasive culture-confirmed meningococcal disease in France, and about 76% of the samples go to theFrench National Reference Center for Meningococci for evaluation.
    • In 2012, of 357 invasive meningococcal isolates, 27% had a significant increase in their MICs (mean inhibitory concentrations) for penicillin G (increasing from 0.125 to 0.5 mg/L), though they still had low MICs for cefotaxime.
    • From 2012-15, 7% of these meningococcal isolates (25 of them) had higher penicillin G MICs (2% of all isolates), harboring a new allele (penA327), which was increasingly detected over this date range and not seen before 2012.
    • This allele additionally conferred a tenfold increase in the MIC for third-generation cephalosporins (C3Gs), and this seems to be specifically from this penA327 allele.
    • This penA327 allele is identical to one found in Neisseria gonorrheae, which is associated with reduced C3G for that species.
    • Several of these meningococcal isolates with the penA327 allele were from an outbreak of invasive meningococcal disease in MSM, from Germany and France.
    • Of note, similar isolates were also reported in patients with meningococcal urethritis, which raises the question of sexual transmission of meningococcus, acting like it was a gonococcus

Commentary:

  • There has been increasing meningococcal resistance to penicillin over the past several years. The French National Reference Center for Meningococci has detected reduced penicillin sensitivity in 26% of 1407 isolates from 2012-2015
  • This high-level N. meningitis resistance to penicillin has largely developed through b-lactamase production from the development of a Pen1 phenotype, leading to the recommendation that third-generation cephalosporins be used for treatment instead of penicillin for therapy. This Pen1 phenotype is mainly caused by alterations in the penA gene, and may well have been due to DNA changes in other Neisseria species. However, it appears that further alterations have led to a variant penA327 allele in a small but increasing number of samples, with attendant reduced susceptibility to C3Gs.
  • The fact that this allele was also reported in meningococcal urethritis, suggest both the possibility of sexual transmission as well as the possibility that there was transfer of resistance from Neisseria gonorrhoeae to Neisseria meningitides, perhaps through coincident infections
  • Although there is reduced susceptibility of N. Meningitidisto third-generation cephalosporins in these variants, the MICs are not high enough to change recommendations on using C3Gs for treatment.
  • The concern, of course, is the emergence of further resistance with clinically significant decreased sensitivity to cephalosporins. As we know, gonorrhea seems to be evolving into an increasingly untreatable disease (see http://blogs.bmj.com/ebm/2016/07/27/primary-care-corner-with-geoffrey-modest-md-gonorrhea-resistance-increasing/ )

 

  1. Increasing Pseudomonas multidrug and carbapenem resistance (see DOI: 10.1093/jpids/piw064). Details:
  • This study looked at all pediatric patients (1 to 17 yo) between 1999 and 2012, reviewing the Surveillance Network Database-USA, which includes microbiology labs serving 300 hospitals across the nation. They defined multidrug resistant Pseudomonas as non-susceptibility to at least 3 of 5 antimicrobial classes (cephalosporins, b-lactam/b-lactamase inhibitor combinations, carbapenems, fluoroquinolones, and aminoglycosides.

Results:

  • 87,613 pediatric pseudomonas aeruginosa isolates were identified, of which 77,349 were tested against the 5 antibiotic classes.
  • 15,653 (20.2%) were multidrug resistant (MDR) and 8763 (11.3%) were carbapenem-resistant (CR). Of these resistant isolates, about 75% were from the respiratory tract, 45% occurred in children aged 13 to 17, and 44% were from the outpatient setting. Males and females were equally affected. The largest number, 24%, were from the West North Central region of the US but there were approximately 15% each from the South Atlantic, West South Central, and East North Central regions.
  • There’s been a linear increase in both CR and MDR over this time period, with MDR increasing from 15.4% to 26% and CR from 9.4% to 20%, both significant trends with p<0.001, representing a 4% annual increase

Commentary:

  • Pseudomonas resistance is mediated through several different mechanisms: enzymes that inactivate b-lactam antibiotics, including cephalosporinases and carbapenemases (leading to resistance to these medications), but also enzymatic and target site modifications (leading to resistance to aminoglycosides and fluoroquinolones), alterations in outer membrane permeability and multidrug efflux pumps (leading to multidrug resistance), the acquisition of mobile elements (plasmids and transposons), and production of protective biofilms. And, Pseudomonas has an unusual ability to survive in harsh environments.
  • The CDC estimates that 51,000 healthcare-associated pseudomonas aeruginosa infections occur in adults and children, of which greater than 6000 (13%) are MDR, and account for more than 400 deaths each year. The majority of cases in children are related to underlying cystic fibrosis. However, of significance, the above analysis excluded patients with CF, and therefore is more representative of the general population.
  • As per many prior blogs (see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ which contains several blogs highlighting worldwide trends in antibiotic resistance/development of superbugs as well as guidelines from the World Health Organization), there is significant concern about increasing antimicrobial resistance. To me this is clearly a very scary and accelerating issue: when I look at any of the infectious disease journals, it seems now that most of the articles are about different microbes displaying increasing resistance. The reason i bring these above 2 articles up is mostly that we in primary care only see occasional articles that make it into the newspapers or general medical literature (e.g. the e. coli suberbug), and may not realize the true extent of the issue. And it is hard to invoke these big picture global public health concerns when treating the individual patient in the office requesting antibiotics.
  • There is some hope: several studies have suggested that aggressive antimicrobial stewardship programs, which restrict the use of broad-spectrum antibiotics, have been shown to be effective in decreasing CR pseudomonas in adult and pediatric populations. And a few studies have found decreasing inappropriate use of antibiotics e.g. see http://blogs.bmj.com/ebm/2016/01/22/primary-care-corner-with-geoffrey-modest-md-antibiotic-overprescribing-and-acute-respiratory-infections/ ). But, as mentioned in several of the prior blogs, overall we need to have an increasingly aggressive program to decrease the development of resistance and, ultimately, to untreatable infections. This approach needs to be worldwide, including: using antibiotics only for clear indications, decreasing widespread antibiotic use in animals just to make them fatter/more profitable (this is 80% of antibiotic usage!!!), using the least broad-spectrum antibiotic that will work, as well as developing perhaps more consistent antibiotic stewardship programs as per the Pseudomonas issue. And we thereby protect our somewhat fragile and (it seems) frequently attacked microbiome….

 

Primary Care with Geoffrey Modest MD: Lessons I’ve Learned From Looking at the Medical Literature

21 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There have been several concerning issues and lessons that I have learned in the process of doing these blogs over the past several years (I am sending out this email/blog as a follow-up to some of the methodological issues and perhaps incorrect assumptions inherent in many clinical studies and their application to actual patients, as noted in the recent blog on placebos. See http://blogs.bmj.com/ebm/2016/11/14/primary-care-corner-with-geoffrey-modest-md-benefits-of-placebo-for-low-back-pain-and-some-random-thoughts/

  • Meta-analyses:
    • There is huge variability in the actual utility of meta-analyses in making clinical decisions. these analyses are mathematical concoctions which try to combine different studies with usually very different people (different inclusion/exclusion criteria, people with different levels/types of comorbidites, different ages, different ethnicities, often different doses of the med being assessed, even somewhat different outcomes measured). And the meta-analyses themselves have different inclusion criteria (minimum number of people in a study that they include, the authors’ assessment of the quality of the study). And they use different statistical analyses (e.g. some do propensity score matching as a means to control mathematically for different patient baseline characteristics; or they may use different basic statistical analyses). Also, in some cases the meta-analysis is overwhelmed by a single very large study (i.e., a meta-analysis with 10 studies, but the one with many more patients will give much more statistical weight to that one study, even if the smaller studies were actually methodologically better). As a result I have seen almost simultaneous meta-analyses on the same subject in different journals coming to different conclusions.
    • There was a really good article looking at the pyramid of the value of different types of clinical evidence (see http://ebm.bmj.com/content/21/4/125.short?rss=1&ssource=mfr , or Evid Based Med2016;21:125-127 doi:10.1136/ebmed-2016-110401 ) which, unlike other “evidence pyramids” in the literature over the past 20 years, dismissed meta-analyses/systematic reviews, and highlighted, for example, that study design itself (i.e. an RCT) does not necessarily mean that it is a “better” study and should be the one influencing clinical practice just because of its design, over a good cohort study (they demonstrate this by their schematic pyramid of evidence-based medicine having wavy lines separating the types of studies, instead of straight-line clear-cut separations of the value of studies by their design. and they do not include meta-analyses/systematic reviews in the pyramid). To me, RCTs are clearly limited by their exclusion and inclusion criteria, and suffer from reductionism (see prior blogs, but basically reducing “n” patients into some mathematical average of, e.g., a 53 year-old patient, 35% female, 78% white, 37% diabetic, with no renal failure and 56% on aspirin……”), and trying to apply the results to a totally different individual patient you are treating with different ethnicity, comorbidities, meds, etc.
  • Guidelines (also not included in the pyramid of the value of evidence-based medicine, above):
    • There has been an unfortunate evolution of clinical guidelines, with a few dramatic shifts over the decades:
      • The older guidelines were written by the NIH or similar governmental organization, with an emphasis on bringing in different experts both within the field and, at least to my experience, some outside of the field (e.g. clinical people), and providing a more consistent, less biased, and independent validation mechanism for the recommendations
      • Perhaps related to ideological or financial imperatives, newer guidelines are more often being channeled back from the governmental agencies to professional societies, creating a few problems:
        • Guidelines may not reach the same conclusions: e.g. the early versions of the Am Diabetic and Am Heart Assn guidelines on blood pressure goal. Then, what is a clinician to do??
        • The professional societies’ guideline-writing groups often do not include practicing clinicians (at least from what I’ve seen), but mostly the higher-ups (i.e., mostly researchers) in the professional societies. There is often a significant financial conflict-of-interest with many guideline-committee members, though this is being watched and reported more now than before, more with some professional societies than others. But, beyond those direct financial/other interests of some of the specialty society leaders, I would guess that it is not easy/comfortable for others within the societies to be critical of them (they are the “leaders”, with disproportionate influence within the writing committee and within the specialty society)
        • And there are a huge profusion of guidelines, from all of these societies, to the point that it is pretty impossible to keep up with them
        • However, I think the real reason that guidelines are not considered part of the “evidence pyramid” noted above is that there is no external validation metric used for these guidelines: there are a group of specialists sitting around a table and making recommendations about how we should treat patients, and with an inherent conflict-of-interest above and beyond those of specific leaders promoting a technique or drug which they may personally benefit from. Is it surprising that the American Urological Association has historically been much more aggressive in pushing for PSA screening? Or the American Cancer Society historically pushing for more cancer screening? Or the American College of Radiology promoting more mammograms?
        • So, the best model to me is reverting to the way guidelines used to be created, as currently done in other countries having a single uniform approach to guidelines (e.g. the NICE guidelines in the UK are pretty exemplary to me: very thoroughly researched, with, I think, pretty unbiased and thoughtful recommendations), using the best external validation metric to promote the best, least-biased recommendations based on known data and relatively unbiased expert opinion and informed by practicing clinicians. probably the best we have now in the US is USPSTF, though they also have an important-to-know filter of usually needing strong support from RCTs to really endorse an approach (e.g., see http://blogs.bmj.com/ebm/2016/08/30/1114/ which does not recommend lipid screening in adolescents, despite what I think is pretty compelling though circumstantial evidence, basically because there are no good 30-40 year studies following 12 year-olds, randomized to diet/exercise/perhaps meds at some point, and looking at clinical outcomes).
  • Using on-line sources for quick guidance (e.g. Up-To-Date, etc.)
    • These are also not on the “evidence pyramid”, for reasons similar to the guidelines issue: the entries are the non-validated opinions of a few individuals about how to evaluate, diagnose and treat patients. There are no upfront disclosures of commercial interest (if you click on an author’s name, then on disclosures in Up-To-Date, you can get the info, but it is a few clicks away, and, I would guess that a busy clinician looking for a quick answer probably does not do this a lot. And then the information is that the author gets money from perhaps a specific drug company. And, I would also guess, most of us primary care clinicians have no idea which meds that drug company makes and therefore which suggested med in the Up-To-Date review might be promoted more…).
    • That being said, I do not know a clinician (including myself) who does not use one or more of these sources pretty often, to get quick guidance about what to do with the patient in front of them….  it is so easy, typically has a review of the relevant studies, and gives very clear guidance. The only issue is bias and reliability…..
  • Misquoting references
    • As mentioned in a few blogs, sometimes the articles misquote references, claiming incorrectly that a previous study came to a certain conclusion. So, it is useful to check the original article when an article makes a statement about another article that seems out-of-line. This is a lot of extra work, though way easier than it used to be (often you can click on a hyperlink of the reference, or do a quick online search. Easier than going to the library…)
    • Even more commonly (still not very common), articles sometime make reference to a citation which is incorrectly cited (i.e., you look at the article cited and it has nothing to do with the author’s point??An error by the author/journal editor in making sure that the citation matches??)
  • Supplemental materials
    • Oftentimes, some of the most important material is relegated to the supplemental material (including important subgroup analyses, methodologic issues, data backing up some of the article’s conclusions, conflicts-of-interest, etc.) which really give lots of insight into the real value of an intervention. These are only accessible online (an issue if you do not subscribe to that journal) and are, I think, a significant impediment for many clinicians to access. In cases where I cannot get a specific article and have emailed the author for a copy, I only get the PDF, and unless I want to pay $30-50 to get the article through the journal (which I am not), I cannot see the supplementary materials.
  • Using not-so-relevant clinical endpoints
    • There has been a trend to using composite endpoints (perhaps to make the likelihood of an intervention’s benefit higher and more likely to be statistically significant) which just don’t make sense, such as combining a really important outcome with much less important ones. For example, a recent blog looked at CPAP for OSA (see http://blogs.bmj.com/ebm/2016/10/03/primary-care-corner-with-geoffrey-modest-md-cpap-does-not-reduce-cardiovasc-risk/ ), assessing CPAP utility for the composite endpoint of hard cardiovascular events plus the development of hypertension. If there were benefit for significant hard cardiovascular events, I would be quite inclined to suggest CPAP for my patients. But if CPAP only decreased hypertension a little (but statistically significant), I would treat that by reinforcing lifestyle changes, or using a med if needed, and would not prescribe CPAP. Or, another example: the ADVANCE study, which looked at tight blood sugar control on the effects on hard CVD outcomes plus diabetic nephropathy. This seems pretty silly. We know from many studies that tight control helps prevent diabetic nephropathy. The more important clinical issue is cardiovascular benefit or harm. And adding a known quantity of decreasing nephropathy into the “composite” endpoint just dilutes/distorts the results. This study really highlights the general issue of lumping together non-equivalent outcomes (it is hard to argue that developing early nephropathy is somehow equivalent to, and should be numerically added to, CV deaths or nonfatal strokes; or in many other studies, lumping together all-cause mortality with need for an additional clinical procedure). I raise these issues as examples, but this is really a very common finding. And this approach of combining endpoints may be worse now, since a large percent of the studies done are designed by drug companies, etc., which have a vested interest in the most positive outcome. And sometimes one cannot disaggregate the individual outcomes without access to the supplementary material….
    • As I have railed about in many blogs, I am really concerned that the FDA accepts surrogate endpoints for some clinical diseases. The most evident one is using A1C as the end-all for new diabetes meds. Personally, I don’t really care so much about the A1c, just what really happens to patients. Many of the new drugs approved do decrease the A1c (though only a little, in most cases), yet have significant and serious adverse reactions (see many blogs in http://blogs.bmj.com/ebm/category/diabetes/ ) which undercut their utility significantly (e.g., as cited in many prior blogs: rosiglitazone does well in lowering A1C, just unfortunately increases cardiac events…)

So, I am writing this blog mostly because I have been doing these blogs for several years now, have been reading lots of articles, have the (perhaps) benefit of seeing the evolution over decades of clinical research and the medical-political-social-economic structure of both the research being done and how it is reported, and am pretty frequently struck by some of the not-often-acknowledged gaps and concerns of that literature and its effect on clinical practice. I would recommend reading the “evidence pyramid” article in the BMJ Evidence-Based Medicine journal referenced above, since it does comment a bit on some of these (and did stimulate me to write this). But, of course, I should also comment that all of the above are my observations (i.e., not validated by an independent group), but at least I have no (i.e., zero) conflicts of interest, other than the bias to a real skepticism in reading articles and guidelines, or of being an early adopter of new meds/procedures…..

Primary Care Corner with Geoffrey Modest MD: Generic Drug Price Variation for Heart Failure Drugs

18 Nov, 16 | by EBM

By Dr. Geoffrey Modest

Most of us, I believe, usually prescribe generic medications to patients, especially for patients who have limited or no insurance and have large out-of-pocket medication costs. A recent study looked at the variability of 3 generic drugs used for heart failure finding dramatic differences within similar geographical areas (see doi:10.1001/jamainternmed.2016.6955).

Details:

  • Data reflect 153 chain and 22 independent pharmacies in a 2-state region (Missouri and Illinois), across 55 zipcodes
  • They compared the cost for uninsured patients of low and high dose digoxin (0.125 and 0.25 mg/d), lisinopril (10 and 40 mg/d), and carvedilol (6.25 and 25 mg bid) for 30– and 90–day supplies.
  • They also correlated the costs with the annual income by zipcode

Results:

  • Median annual income within pharmacy zipcodes was $53,122, with a range of $10,491 – $112,017
  • The number of manufacturers was about 8 for each drug
  • Only one chain had consistent pricing across its stores
  • For a 90-day supply of the highest dose of the meds:
    • Digoxin 0.25mg varied from $10 to $910.99, with median $114.99
    • Lisinopril 40mg varied from $6.75 to $223.95, with median $34.25
    • Carvedilol 25mg varied from $6 to $208.44, with median $41.23
    • And, for all 3, $30 to $1,144.98, with median $180.46
  • Only 1.7% of pharmacies charged less than $25 for 30-day supply and 5.3% less than $100 for 90-day supply.
  • Overall, they found:
    • Pharmacy type (chain vs. independent) was not significantly associated with pricing
    • Pharmacy pricing did not vary by median annual income of the area, whether median income was $85,883, $59,347 or $31,032
    • Pricing did not vary significantly by state, or clustering by zipcode (review of their figure showed very close proximity of pharmacies with very high and very low price drugs)

Commentary:

  • So, pretty shocking differences in generic drug pricing, independent of the income of the neighborhood, the type of pharmacy, or drug dose/duration of therapy.
  • And, it is clear from several studies that the cost of medications does correlate with medication adherence.
  • We do seem to have a counterintuitive (and counterproductive) system in the US: patients without insurance, often those with the least income, have to pay much more for medications than insurance companies negotiate (ie, the above prices are likely much higher than an insurer would pay, even with the patient co-pay added).
  • This study only looked at 3 drugs, and though more data is needed on other meds, my own experience is that there is large variability in pricing for other drugs as well

So, bottom line: I think the study reinforces that patients without insurance really should call around to different pharmacies to check pricing. Patient should understand that there are potentially huge variations in drug costs from one pharmacy to another, even in the same neighborhood. And we really should move to a more transparent and consistent system of drug pricing in this country.

Primary Care Corner with Geoffrey Modest MD: Lifestyle Changes and Genetic Risk for CAD

17 Nov, 16 | by EBM

By Dr. Geoffrey Modest

A recent study looked at the relative effects of genetic risk and healthy lifestyle in the development of coronary artery disease (see DOI: 10.1056/NEJMoa1605086).

Details:

  • 3 prospective cohorts were followed: the Atherosclerosis Risk In Communities (ARIC, with 7814 white people between the ages of 45 and 64), the Woman’s Genome Health Study (WGHS, with 21222 white female health professionals), and the Malmo Diet and Cancer Study (MDCS, with 22389 Swedish people aged 44 to 73 and free from prevalent cardiac disease). Also included were 4260 people the cross-sectional BioImage Study who had genetic/risk factor data and had coronary artery calcium (CAC) scores
  • They evaluated these people for up to 50 single–nucleotide polymorphisms (SNPs) known to be associated with coronary artery disease, and then derived a polygenic risk score based on the number of risk alleles at each SNP, multiplied by the sum of the literature-based clinical effect size.
  • They also assessed 4 lifestyle behaviors: no current smoking, BMI <30, physical activity at least once a week, and a healthy diet pattern (consisting of increased amounts of fruit, nuts, vegetables, whole grains, fish, dairy, as well as reduced amounts of refined grains, processed meats, red meats, sugar sweetened beverages, trans fats, and sodium)
  • A favorable lifestyle was defined as at least 3 of the 4 healthy lifestyle factors, with an intermediate lifestyle being 2 of these factors.

Results:

  • 1230 cardiac events were observed in the ARIC cohort over 18.8 years, 971 in the WGHS cohort over 20.5 years, and 2902 in the MDCS cohort over 19.4 years
  • A risk gradient was noted across quintiles of genetic risk, pretty consistently among the studies, with a hazards ratio of 1.91 comparing the top vs. bottom quintile of risk scores, reflecting a 91% higher attributable genetic risk, controlling for age, sex, self-reported education level, and analysis of ancestry when available
  • Levels of LDL cholesterol were only modestly increased across categories of genetic risk, and genetic risk scores were independent of other cardiometabolic risk factors as well as the 10- year predicted cardiovascular risk
  • A family history of coronary disease was an imperfect surrogate for genotype-defined risk [perhaps part of the issue: several older studies i have seen have found pretty dramatic discordance between elicited family history of heart disease and actual known heart disease events in the family members, up to 35-40%; the Framingham study found a 17% discordance.]
  • Each of the lifestyle factors were associated individually with decreased coronary risk: non-smoking with a 44% decreased risk, BMI <30 with a 34% decrease risk, regular physical exercise with a 12% decreased risk, and a healthy diet with a 9% decreased risk
  • People with unfavorable lifestyles (<2 of the 4) had higher rates of hypertension and diabetes, higher BMI, and less favorable lipids; overall they had an adjusted hazard ratio of cardiac disease of approximately 2 in each of the three prospective cohorts (i.e., twice the risk).
  • Within each genetic risk category, lifestyle factors were strong predictors of coronary events.
    • Adherence to a favorable lifestyle (at least 3 of the 4 factors) vs. an unfavorable lifestyle (<2) was associated with a 45% lower relative risk in the group at low genetic risk, a 47% lower relative risk among those when intermediate genetic risk and 46% among those at a higher genetic risk. [i.e., the relative risk was equivalently lower in each genetic subgroup with more favorable lifestyle]
    • Among people at high genetic risk, in the 3 prospective cohorts the 10-year coronary event rates were also approximately twice as high in those with unfavorable vs. favorable lifestyles.
  • Further analysis showed that those with high genetic risk but healthy lifestyles had about the same number of cardiac events as those with low genetic risk but unhealthy lifestyles in each of the 3 prospective cohorts, though this was partially explained by differences in traditional risk factors
  • There were limited data for the black population and generally less well-validated genetic loci for coronary disease, although evaluating the black cohort in the ARIC study yielded similar findings
  • In the BioImage study, both genetic and lifestyle factors were associated with higher CAC scores, and within each genetic group there was a significant trend toward decreased CAC scores in those with a healthier lifestyle

Commentary:

  • This study validates that both genetic risk as well as lifestyle are continuously related to cardiac events, and that the genetic risk is largely independent of traditional cardiac risk factors
  • But, this study really undercuts genetic determinism. In fact, there was the same relative decrease in cardiac risk in each of the genetic subgroups (high vs. low genetic risk) with improved lifestyle. And, in terms of absolute risk, those at the highest genetic risk had much more benefit from a healthy lifestyle change than those of lower genetic risk.
  • One general concern I have, tangentially related to the above, is with the availability of genetic analyses for the general population (e.g., 23andme, which advertises “discover what your 23 pairs of chromosomes say about you”, and costs only $199). My concerns are in part that we don’t really know how to interpret many of these genetic findings prospectively, but also that this analysis may reinforce a sense of genetic determinism in the population.
  • It was also a little surprising that the benefits for the individual lifestyle markers were what they were. We do know from prior studies that smoking cessation is the single most beneficial individual intervention in decreasing cardiac risk, as also suggested in this study which found that current non-smoking was associated with the lowest cardiac risk . What was most surprising to me was that the benefit of exercise and healthy diet were not so profound: I suspect that the quantification of diet and exercise was likely not that accurately represented as a bimodal, all-or-none issue (e.g., unclear what the cutpoint was for defining a healthy vs. unhealthy diet, and using one day of exercise a week without even quantifying the amount/type of exercise makes these lifestyle markers hard to interpret, especially as compared to smoking or BMI which have clear bimodal cut-points)

So, I think this study provides some important information in dealing with patients. I have certainly seen many patients who feel that they are destined to die from heart disease because of their family history. This study provides a tool to speak even more convincingly with patients, in that those at higher genetic risk actually achieve the most benefit by improved lifestyle.

Primary Care Corner with Geoffrey Modest MD: Cardiac Drug Interactions with Statins

16 Nov, 16 | by EBM

By Dr. Geoffrey Modest

The American Heart Association just published their recommendations for managing drug-drug interactions between statins and other drugs used for cardiovascular disease (see DOI: 10.1161/CIR.0000000000000456 ). I bring this up because statins are such an important drug that we use all the time, drug-drug interactions overall are common (leading to about 3% of hospital admissions, and the result of many annoying flags in electronic medical records) and because this review goes into detail on the mechanisms of these interactions (whether through the cytochrome P-450, CYP450, system of oxidative enzymes, or those interactions involving permeability glycoprotein P-gp, a superfamily of membrane-associated ATP-binding cassette-transporters, also called multidrug resistance-1; this article gives a good review of these systems, the latter of which was pretty much unknown to me prior to seeing this article….), and the article comments on the likely clinical importance of these interactions. Of note, I did not include recommendations for fluvastatin or pitavastatin, since these seem to be used rarely. Here is a brief review of the important/relatively common drugs used in primary care:

  • Amlodipine: minor interaction with lovastatin and simvastatin (for the latter, 1.8-fold increase in simvastatin level, with recommendation to limit simvastatin dose to 20mg)
  • Colchicine: variable interaction with all of the statins, though combination “may be considered”. Monitor muscle toxicity closely. Of note, colchicine itself can cause myopathy, so can be hard to differentiate from statin-induced. Colchicine does not seem to impair CYP450 system though does seem to compete for P-gp-mediated efflux. Not much clinical data on the interaction with statins, but likely that best tolerated (based on the effect on P-gp) would be rosuvastatin, lovastatin, or pravastatin. And probably best to use lower doses of colchicine: 0.6-1.2 mg loading dose and 0.3-0.6 mg/d maintenance
  • Digoxin: not dependant on the CYP450 system. atorvastatin increases digoxin level 1.2-fold. Combo is reasonable with any statin without dose adjustment. But best to monitor digoxin levels in those on atorvastatin, esp if on higher doses.
  • Diltiazem: minor interaction with atorvastatin, but moderate with lovastatin and simvastatin (about 4-fold increase in statin levels). Limit lovastatin dose to 20mg and simvastatin to 10mg
  • Fenofibrate: insignificant interaction with all (though no data on lovastatin)
  • Gemfibrozil: minor interaction with atorvastatin and rosuvastatin. Avoid combo with lovastatin, pravastatin, and simvastatin
  • Verapamil: moderate interaction with lovastatin and simvastatin. Limit dose of lovastatin to 20mg and simvastatin to 10mg
  • Warfarin: 30% increase in INR with simvastatin, variable effects with lovastatin, rosuvastatin. But monitor INR with initiation or change in dose of any statin [which i think is reasonable with almost any new drug…]

A brief comment on cardiac and other drugs used less frequently in primary care:

  • Amiodarone: metabolized by both CYP34A and CYP2C8, as well as substrates of P-gp efflux transporter. Not use simvastatin (and definitely not more than 20mg) or lovastatin (not more than 40mg). rest are okay
  • Dronedarone: similar to amiodarone, but recommended to use simvastatin and lovastatin at even lower doses (e.g. not more than 10mg)
  • Ranolazine: best to use rosuvatatin, atorvastatin, pravastatin. FDA recommendation to limit dose of simvastatin to 20mg
  • Ticagrelor: can use atorvastatin; if use simvastatin or lovastatin, then no more than 40mg/d; no reported interactions with other statins
  • Conivaptan (a vasopressin receptor antagonist): not use lovastatin/simvastatin; best to use atorvastatin, pravastatin, or rosuvastatin. Tolvaptan can be used with any statin
  • Immunosuppressants: avoid combos of lovastatin or simvastatin with cyclosporine, everolimus, tacrolimus; best to use rosuvastatin up to 5mg, atorvastatin up to 10mg, pravastatin up to 20mg
  • Sacubitril/valsartan: limited data, minimal metabolism by CYP450 system, some increase in atorvastatin levels but no reported adverse clinical effects
  • Ivabradine: limited data, but extensively metabolized by CYP34A system (so, I would avoid simvastatin/lovastatin)

Commentary:

  • This review was helpful to me for a few drug-drug interactions in particular
    • Gemfibrozil: my prior held belief (and the 2013 American Heart Association guidelines statement) was that we should not use the combo of gemfibrozil with any statin, because of significant risk of myositis with the combo  (also some increased risk of hepatotoxicity). This created a bit of a problem, since studies do suggest that fenofibrate seems to be much less effective in lowering triglyceride levels and does not seem to have the same cardiovascular benefits of gemfibrozil (e.g., comparing the FIELD trial of fenofibrate and the VA-HIT or Helsinki trials with gemfibrozil; also a meta-analysis confirmed that fenofibrate is a poor cousin to gemfibrozil). These new guidelines still prefer using fenofibrate, since large studies with the statin/fenofibrate combo do not show an increased toxicity; and they suggest using atorvastatin or rosuvastatin at a lower dose (FDA suggests max rosuvastatin of 10mg/d) if use gemfibrozil. But at least the combo of gemfibrozil and atorvastatin or rosuvastatin is now acceptable.
    • It really is okay to use simvastatin with amlodipine, despite my electronic record and pharmacist yelling at me when I have tried to do so. Though, that being said, it does seem that atorvastatin is overall better tolerated in terms of drug-drug interactions (rosuvastatin and pravastatin are also quite good). The reason is that simvastatin and lovastatin are metabolized in the CYP3A4 system, the most common enzyme system in drug metabolism, and atorvastatin is metabolized by this system less so. Rosuvastatin is metabolized in the less commonly used CYP2C9 system. Pravastatin is not metabolized through the CYP450 system at all, but is by the OATP enzymes (organic anion-transporting polyprotein)
  • So, overall this guideline does present a more detailed (and complex) characterization of the drug-drug interactions between statins and other cardiac meds, and is pretty helpful with some very specific guidance. Unfortunately, it does not deal with non-cardiac meds (and, it turns out, that we in primary care do sometimes prescribe non-cardiac meds…)

Primary Care Corner with Geoffrey Modest MD: NSAID Use and Risk of Heart Failure

16 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent large case-control study confirming several other studies showing a significant risk of heart failure with the use of NSAIDs (see doi.org/10.1136/bmj.i4857).

Details:

  • Five large population health care databases from Europe, with 92,163 hospital admissions for heart failure, matched with 8,246,403 controls.
  • Mean age 77, 45% men, patients who developed heart failure were more likely to have history of cardiovascular disease (acute MI in 3.3 vs 1%, atrial fibrillation in 5.0 vs 1.3%, valvular heart disease in 2.6 vs 0.9%, hyperlipidemia in 20.4 vs 14.1%, diabetes in 19.4 vs 8.8%; and be on more meds (ACE/ARB in 42.1 vs 24.6%, b-blockers in 24.4 vs 15.2%, diuretics in 53.2 vs 18.6%)

Results:

  • Current use of any NSAID in the preceding 14 days (vs past use greater than 183 days in the past) was associated with a 19% increase of hospital admission for heart failure with OR 1.19 (1.17 to 1.22)
  • In terms of specific NSAIDs, odds ratios of first admissions for heart failure:
    • ketorolac: OR 1.94 (1.71 – 2.19)
    • indomethacin: OR 1.52 (1.31 – 1.77)
    • diclofenac: OR 1.21 (1.16 – 1.26)
    • ibuprofen: OR 1.15 (1.08 – 1.21)
    • naproxen: OR 1.19 (1.08 – 1.31)
    • nabumetone: OR 1.07 (0.81 – 1.43), nonsignificant
    • celecoxib: OR 0.95 (0.89 – 1.02), nonsignificant
  • Almost all of these associations were more profound in those with prior history of heart failure admissions (most extreme was for ketorolac, which developed an OR of 5.09; though the association with naproxen and diclofenac became nonsignificant in those with prior history)
  • There were pretty evident dose-response curves, with the higher doses of NSAIDs associated with more heart failure for many of the NSAIDs. This was measured using Daily Dose Equivalents (DDD), which is the “average maintenance dose”, not specifically defined for each NSAID, but they found the following, with medium dose being 0.9-1.2 DDD, high 1.3-1.9, and very high (>=2): [note: there were only 2 databases which provided this info, and the numbers of people in some of the categories was small]
    • Diclofenac went from insignificant increase in heart failure at low to medium dose, then to OR 1.1 for high and 2.2 for very high
    • Indomethacin increased with increasing dose (p<0.001) for the trend, with OR 1.7 for medium and high dose, jumping to 2.5 for very high, but too wide a confidence interval to make it significant
    • Naproxen OR 1.3 for high and 1.4 for very high
    • Not a clear trend (the very high DDD had OR 1.9, but very wide confidence intervals)
    • Celecoxib: no trend

Commentary:

  • This study basically confirms that NSAIDs are associated with heart failure, and that some are better than others (though I should add that those who developed heart failure were sicker and had more co-morbidities that would make heart failure more likely, even though there were attempts to mathematically control for that). Of note, this study and some others have found that celecoxib (as opposed to pretty much any of the other COX-2 inhibitors) seems to be better [and other studies have found that it does not seem to provoke MIs as does rofecoxib/Vioxx]
  • Most of the above associations applied to men and women, though were stronger in men
  • The dose response curve found with several of the meds (higher dose with more heart failure) serves to reinforce the likely causality of the association
  • The likely mechanisms are related to inhibition of prostaglandin synthesis, which leads to increased peripheral resistance (and blood pressure, another important adverse effect), decreased renal perfusion/GFR (and renal dysfunction, yet another), and decreased sodium excretion/sodium retention
  • As many of you know, I am very concerned about long-term use of NSAIDs and PPIs, in part because they are used so frequently (and are available OTC, which also creates the impression that they must be safe) and because of their litany of significant adverse events (for some of my previous blogs on NSAIDs, see links below). And, of course, the reason they are used so much is because they are really effective. Which makes our tasks harder: how to convince patients to use less toxic meds
    • By downgrading NSAIDs, preferably to nonpharmacologic therapies such as PT or yoga; or through local injections, often given once or infrequently, which do spare systemic side effects in general
    • And downgrading PPIs to H2-blockers or calcium antacids along with sometimes helpful dietary changes

See http://blogs.bmj.com/ebm/2015/07/29/primary-care-corner-with-geoffrey-modest-md-nsaid-warning-by-fda/ for FDA warning about NSAIDs and increased risk of heart attack or stroke

See http://blogs.bmj.com/ebm/2015/06/01/primary-care-corner-with-geoffrey-modest-md-h-pylori-and-nsaids-increased-gi-bleeding/ for blog on the role of H pylori in increasing the risk of GI bleeds in those on NSAIDs

See http://blogs.bmj.com/ebm/2014/05/02/primary-care-corner-with-geoffrey-modest-md-nsaid-and-atrial-fibrillation/ for increased risk of afib with NSAIDs

Primary Care Corner with Geoffrey Modest MD: Meningococcal vaccine in HIV-positive patients

15 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There are 2 potentially very serious bacterial infections, both with functional vaccines available but not previously recommended, that seem to be more common in HIV infected patients: HIB (haemophilus influenzae type B) and meningococcus. The Advisory Committee on Immunization Practices, ACIP,  just came out with recommendations to immunize HIV-positive patients against meningococcus.

Details:

  1. For the HIB infection: I had been immunizing all HIV patients with HIB vaccine until a few years ago, based on a case-control study about 20 years ago showing a higher prevalence of invasive HIB infections in HIV positive patients. Though the data on efficacy were lacking, it seemed to me that the potential benefit far outweighed the very low risk of this tried-and-true vaccine. The current feeling, from my reading, is that while HIV may be a risk factor for invasive HIB infections, the incidence of HIB infections overall has plummeted due to the aggressive HIB immunizations of children, dramatically decreasing the HIB reservoir and shifting the serotype of prevalent H flu infections dramatically away from typable to nontypables. So, it does seems unnecessary to immunize. But, it still may still be reasonable to vaccinate those patients who come from and return to countries without universal pediatric HIB immunization.
  1. Meningococcal vaccine: I also began immunizing my HIV patients with meningococcal conjugate vaccine several years ago, after the outbreak of meningococcal disease in HIV-positive people in New York, though I stopped a couple years ago because of strong and persistent statements by the CDC not to do so. The new recommendations, however, are that all HIV-infected persons be immunized pretty aggressively (see https://www.cdc.gov/mmwr/volumes/65/wr/mm6543a3.htm?s_cid=mm6543a3_x ).
  • Those < 2 years old should get MenACWY-CRM (Menveo) at 2, 4, 6, and 12-15 months, or get MenACWY-D (Menactra) at ages 9-23 months and then 12 weeks later (with the caveats that this last one be given: only if >4 weeks after finishing the pneumococcal conjugate vaccine and either before or concomitantly with DTaP — see below)
  • Those > 2 years old and not previously vaccinated should get a 2-dose primary series of the conjugate vaccine (either of the above), 8-12 weeks apart
  • Those who had most recent vaccine dose < age 7 years should get a booster 3 years later, then every 5 years thereafter
  • Those who had most recent vaccine dose > age 7 years should get a booster 5 years later, and every 5 years throughout life.
  • The immunogenicity study (comparing a single vs a series of 2 vaccines in patients with CD4 percent>15%) noted serious adverse events in 2.2-6.5% six weeks post-vaccination, the number of adverse events being inversely related to CD4 percent, and only one of the serious adverse events (ocular pain) felt to be related to MenACWY-D. A study in kids aged 2-10 found 5% had a serious adverse event, but none felt to be attributable to the vaccine
  • Overall, from a lifetime perspective, vaccination was calculated to lead to the prevention of approx 122 cases of meningococcal disease and 23 deaths, and 385 quality-adjusted life years (QALY) could be saved, with mean cost of $732,000 per QALY if the primary series of vaccines and lifelong boosters every 5 years were given.

Commentary:

  • The risk of meningococcal infection in HIV patients, from data from the US, UK, and South Africa, is 5-13x that of non-HIV infected, with prevalence of 3.6-6.6 per 100,000, and with a case-fatality rate that is a bit mixed: those with HIV in South Africa had about twice the meningococcal case fatality rate (20% vs 11%), though this was not found in New York or the UK.
  • The risk of meningococcal disease is higher in those with high viral loads or low CD4 counts, though the immunogenicity of the vaccine is about 50% lower in those with lower CD4 counts (i.e., better to wait until the CD4 increases in those with uncontrolled infections, though unclear exactly what the cut-point here is from the studies. The one study the MMWR quoted used the CD4 cutpoint of 200 from a New York study, finding a 5.3-fold increased risk with CD4<200). Similar risk in men and women.
  • The majority of meningococcal infections in HIV-infected people are of serogroups A,C,W, and Y. One issue is that the largest database, the passive National Notifiable Diseases Surveillance System, does not include HIV status. The Active Bacterial Core surveillance (ABCs), a smaller database from 10 sites and representing 14% of the US population, does include HIV status. Based on these somewhat limited data, there were 62 cases of meningococcal disease in HIV-infected patients from 1995-2015, 13% were serogroup B and 10% were of unknown serotypes; 92% of cases were in people aged 20-59 years old
  • They do note that the only licensed vaccine for those >55 years old is the meningococcal polysaccharide vaccine; they still recommend the MenACWY conjugate vaccine, based on limited data.
  • The recommendations for infants 2-23 months are complex: they recommend the MenACWY-CRM and not the MenACWY-D because of potential immune interference with the PCV conjugate vaccine with the latter, as well as potential interference of DTaP with MenACWY-D if the MenACWY-D was given 30 days after the DTaP, but not if the 2 are given simultaneously or if the MenACWY-D is given first
  • Ndata on efficacy or adverse events if meningococcal vaccine given during pregnancy or lactation
  • So, the bottom line for me: I do plan to restart giving HIB vaccine to HIV-infected patients who are going back and forth to countries without routine HIB vaccination for kids (not CDC recommended, but makes sense to me). in addition, i will adopt the meningococcal conjugate vaccine according to the ACIP schedule above, including the booster immunization every 5 years, though i will wait until the CD4 increases to a level of >15% or until it plateaus at its highest CD4 percent (using the CD4 percent, as in the studies they quoted: there was no mention of the absolute CD4 count). I will also wait until the viral load is suppressed, since the limited data found a better response if the viral load was lower, in one of the studies if <400. The CDC does not mention anything about meningococcal serogroup B vaccination, but i would consider using the meningococcal B vaccine if there were a local outbreak of serogroup B infections (though my literature search revealed nothing on the immunogenicity or efficacy of that vaccine in HIV-positive patients).

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