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Archive for April, 2015

Primary Care Corner with Geoffrey Modest MD: USPSTF breast cancer screening recommendations

30 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

The US Preventive Services Task Task Force just published a draft recommendation for breast cancer screening in women after age 50 (see here), as follows.

For women 50-74 years old, screening mammography every 2 years, grade B recommendation (moderate certainty that there is net benefit):

–meta-analysis suggests that screening 10,000 women age 50-59 over 10 years will result in 8 fewer breast cancer deaths; screening 10,000 women age 60-69 over 10 years will result in 21 fewer breast cancer deaths. These data are from really old studies. It is likely that current screening may detect more cancers but also that current treatment will decrease the deaths

​–harms of screening: most important is overdiagnosis and overtreatment. Hard to know for sure what the % is, depends on modeling methods used, but it is likely that the increased sensitivity of mammography screening leads to more overdiagnosis. Estimates range from 0% to 54%, but the accepted number is that about 20% (1 in 5 women) are treated for a cancer that would never have been discovered without the mammography and would not have led to health problems.  The other screening harm is false-positives leading to more imaging/biopsy. The data from the Breast Cancer Surveillance Consortium (BCSC, collaborative network of 5 mammography registries plus 2 others with linkage to tumor registries): per 10,000 women screened once: 

–age 50-59 — 932 false positives; 60 biopsies performed for each case of invasive cancer; 11 false-negative mammograms (missed cancers). 

–age 60-69 — 808 false positives; 30 biopsies for each case of invasive cancer; 12 false-negative mammograms. 

–age 70-74 — 696 false positives; 30 biopsies for each case of invasive cancer; 13 false-negative mammograms. 

–frequency of screening: no direct data from clinical trials, but looking at the current trials with screening intervals o f 12 to 33 months, there was no clear trend to benefit in more frequent screening for different starting ages. Observational evidence that there was no difference in breast cancer deaths in women >50 screened biennially vs annually

​–when to consider stopping screening: this data is based on modeling, since there are inconclusive data on 70-74 yo women. USPSTF does not recommend screening 70-74 yo women with moderate to severe comorbid conditions (moderate=cardiovascular disease, paralysis, diabetes; severe=AIDS, COPD, liver disease, renal failure, dementia, CHF, MI, ulcer, rheumatologic disease and combo of moderated conditions).

For women 40-49 years old, grade C recommendation (selectively offer screening, based on professional judgment and patient preferences. moderate certainty that net benefit is small vs more common harms). Still suggesting biennial screening.

–breast cancer deaths avoided by repeated screening of 10,000 women over 10 years = 4.

–harms of mammography for 10,000 women screened once: for age 40-49: 1,212 false positives; 100 biopsies done to find 1 case of invasive cancer; 10 false-negative mammograms. 

–frequency of screening: as with 50-74 year olds (above)

–consider starting at age 40 especially in women with first-degree relative (parent, child, sibling) with breast cancer (increases risk 2-fold)

Comparing starting at age 40 vs age 50:

–life-time benefits for biennial screening mammograms per 1,000 women (note: this is per 1,000 women vs the 10,000 in other data above)

–age 40-74: reduced breast cancer deaths 8; life-years gained: 152.  harms: false positive test 1,529; unnecessary biopsies 204; overdiagnosed breast cancers 20.

–age 50-74: reduced breast cancer deaths 7; life-years gained: 122.  harms: false positive test 953; unnecessary biopsies 146; overdiagnosed breast cancers 18.

–10-year cumulative probability of false positive​ mammogram or biopsy:

–begin at age 40: annual mammograms with 61.3% having false positive, 7.0% with false-positive biopsy recommendation

Biennial mammogram with 41.6% having false positive, 4.8% with false-positive biopsy recommendation

–begin at age 50: annual mammograms with 61.3% having false positive, 9.4% with false-positive biopsy recommendation

​Biennial mammogram with 42.0% having false positive, 6.4% with false-positive biopsy recommendation

For women age >75: insufficient evidence, though some models do suggest continued benefit after age 74 (these are all mathematical models, no real clinical data)

Tomosynthesis (3-D digital mammography): insufficient data for use as primary breast cancer screening strategy, though there may be reduced recall rates for false-positives, and does expose women to twice the radiation

Breast density: BCSC data suggest that 25 million women (43%) have heterogeneously or extremely dense breasts, and % is highest in those age 40-49. increased breast density is associated with higher risk of breast cancer (though not increased risk of dying from breast cancer), and is associated with lower sensitivity (from 87% to 63%) and specificity (from 96% to 90%) of mammography. So, women with increased breast density are at increased risk of false-positive test, unnecessary biopsy, and false-negative test. For women aged 40-49 (but not other groups), there are data suggesting that those with extremely dense breasts have more benefit from annual vs biennial screening.

Other modes of screening, esp in women with dense breasts (eg, breast ultrasound, MRI) — insufficient evidence to recommend.

One of the big unknowns with breast cancer screening is around overdiagnosis and specifically with DCIS (ductal carcinoma in-situ). The incidence of DCIS increased dramatically now that mammography is routine, from 6 to 37 cases/100K women/yr. DCIS is not necessarily a cancer (there is a movement underfoot to reclassify it as not a cancer)​ in that it is in most cases localized/confined to the mammary ductal-lobular system and does not metastasize, there is no good way to differentiate the majority of regular DCIS from the unusual ones that do metastasize, and the current treatment of DCIS is pretty aggressive (lumpectomy/mastectomy, then maybe tamoxifen) — ie, this is a big hole in our knowledge base and needs more research. Another big issue is the ethnic/racial disparity: African-American women have a slightly lower incidence of breast cancer (127 cases/100K, vs 133 cases/100K in white women) yet a significantly higher mortality. ??role of socio-economic status/access to care (which is undoubtedly part of the issue in many areas of the country) vs biology — are there underlying biological differences leading to the finding that Af-Am women tend to have more aggressive and treatment-resistant tumors (eg with triple-negative phenotypes, and more dysplastic tumors), which, by the way, tend to be less amenable to screening?

So, I think these recommendations overall are pretty appropriate. The efficacy of screening is higher in the older age group (median age of cancer diagnosis is 61, and the above numbers confirm increased utility in the 60-69 yo age group). Based on modeling data a few years ago, I have been advocating biennial exams in order to decrease the risk of radiation exposure, and most of my patients are very open to that. I do offer screening at age 40, though I try to make it clear that this is an individual choice, that though there may be some benefit, there are also clear risks of overdiagnosis/increased likelihood of needing more xrays (additional radiation) and biopsies.

For past blogs, see:

Here for a review of the inconsistencies in breast biopsy interpretation

This one goes through more about the risks of screening, utility of using meds in high risk women as cancer prevention, and the need to look into environmental toxins to prevent breast cancer from happening in the first place

This one also critiquing the low efficacy of screening (it should be done, but overall it is not having a huge impact on breast cancer survival)​.

Primary Care Corner with Geoffrey Modest MD: E-cigarettes

27 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

So, no great surprise. E-cigarettes are taking over our youth…  The latest MMWR reviewed tobacco use in middle and high school students in the US, from 2011-2014, revealing profound changes (see here​ for full MMWR report).

In brief:

 –the CDC and FDA reviewed data of trends in current tobacco use (defined as: use >=1 day within the past 30 days) in middle schools (grades 6-8) and high schools (grades 9-12)

–overall, 24.6% of high school students reported current use of a tobacco product, and 12.7% reported use of >= 2 tobacco products

–in 2014, e-cigarette were the most commonly used tobacco product in middle (3.9%) and high (13.4%) school students, with significant increases in both e-cigarettes and hookahs (p<0.05), and decreases in cigarettes and cigars (so, in sum, no change in overall tobacco use, meaning that 4.6 million students are still exposed to tobacco).

–overall for high schoolers: e-cigarettes 13.4%, hookahs 9.4%, cigarettes 9.2%, cigars 8.2%, smokeless tobacco 5.5%, snus 1.9%, pipes 1.5%. E-cigarettes were the most common tobacco product used by non-Hispanic whites, Hispanics, persons of non-Hispanic other races; but not in non-Hispanic blacks, where cigars were the most used.

–overall for middle schoolers: e-cigarettes 3.9%, hookahs 2.5%, cigarettes 2.5%, cigars 1.9%, smokeless tobacco 1.6%, snus 0.5%, pipes 0.6%

–see rather striking graph at bottom for high school students. that for middle school is in MMWR, but is basically the same but with lower numbers.

So, no huge surprise. it is pretty clear that e-cigarette marketing and packaging (with an ever-increasing array of seductive flavors) is targeted to kids. And this brings up a few very significant issues. One is the neurobiology– that the adolescent brain, when exposed to nicotine, may be more susceptible to long-term adverse consequences and addiction. Another is that the marketing and acceptance of e-cigarettes is (as predicted) un-demonizing tobacco products. There have been dramatic and steady gains in decreasing cigarette smoking over the decades, despite advertising overall and in particular to kids. the large tobacco companies have clearly shifted their approach, at least in the US and Europe (as I understand), to focusing on the socially- and in many cases governmentally-more acceptable e-cigarettes.

See prior blogs for more details:

This one highlights some of the political and medical consequences of e-cigarettes. This one highlights some of the contaminants found in some e-cigarettes made in China (where 90% of the worldwide e-cigarettes are made)

Here is graph of tobacco use in high-schoolers:

graph(CDC, 2015).

Primary Care Corner with Geoffrey Modest MD: PCSK9 inhibitors and general observations

24 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

Two articles came out in the New England Journal of Medicine regarding PCSK9 inhibitors and impressive decreases in LDL levels but also finding significant decreases in cardiovascular events. PCSK9​ (proprotein convertase subtilisin-kexin type 9) is a protease which degrades hepatic LDL receptors (I have appended one of my blogs from 2012 at the bottom, which goes into a tad more detail). Overall these PCSK9 inhibitors work in some ways similar to statins, by increasing hepatocyte LDL receptor activity.

 

  1. Alirocumab is a monoclonal antibody which inhibits PCSK9 and reduces LDL levels. A study of quite high-risk patients with LDL>70 mg/dl on a statin at the maximum tolerated dose were assigned to biweekly subcutaneous alirocumab vs placebo over a period of 78 weeks (see N Engl J Med 2015;372:1489-99).

Untitled

Details:

–2341 patients, mean age 60.5, 62% male, 93% white !!), BMI=30, 18% with heterozygous familial hypercholesterolemia, 69% with CAD, 41% with CAD-risk equivalent, 35% with diabetes, 21% smoker. 47% on high-dose statin, rest on “any statin” and 28% with “other lipid-lowering therapy”, mostly ezetimibe. baseline LDL 122 mg/dl​, HDL 50 mg/dl, fasting TG 132mg/dl, lipoptrotein(a) [Lp(a)] of 21.

–at week 24 there was a dramatic 62% decrease in calculated LDL levels with the drug (p<0.001) down to 48 mg/dl (the effect persisted for the full 78 weeks, if one includes only patients who continued to take the drug), and decrease in Lp(a) of 28% (which i believe only really happens with niacin, and does not with statins). HDL increased 5%.  80% of the patients on the drug had an LDL<70 mg/dl. no diff in LDL reduction in the different groups of patients (ie, whether they had familial hypercholesterolemia or other risk groups).

–in post-hoc analysis of prespecified cardiovascular outcomes: rate of major cardiovascular events (death from CAD, nonfatal MI, fatal or nonfatal ischemic stroke, unstable angina) was 1.7% vs 3.3% [HR=0.52 (0.31-0.90), p=0.02]

–adverse effects: injection-site reactions (5.9% vs 4.2%), myalgia (5.4% vs 2.9%), neurocognitive effects of confusion/amnesia/memory impairment (1.2% vs 0.5%), eye events (2.9% vs 1.9%) Study drug/placebo discontinuation rates: 28.2%/24.5%

–of the 37% of patients on the drug who achieved an LDL<25 mg/dl, there was no difference in adverse events, including neurocognitive.

  1. Evolucumab, also a monoclonal antibody which inhibits PCSK9 and is administered subcutaneously biweekly,was used in another study (see N Engl J Med 2015;372:1500-9). patients on standard therapy were randomized to evolucumab or placebo and followed 11 months.

Untitled2

Details:

 –4465 patients, mean age 58, 50% male, 86% white, 47% from the US/40% Europe/13% Asia Pacific or South Africa. risk factors: hypertension 52%, diabetes 13%, metabolic syndrome 33%, current smoker 15%, and estimated CAD risk of >10% in 10 years in 45%. 20% had prior CAD, 9% with cerebrovasc or periph vasc disease, 70% on statin (27% high-intensity), 14% on ezetimibe. baseline LDL 120 mg/dl, HDL 51 mg/dl, TG 120 mg/dl (so, this was a less sick population than the first study)

–primary endpoint: adverse events. secondary endpoint was LDL decrease. prespecified exploratory outcome with adjudicated cardiovascular events = death, coronary events (MI, unstable angina requiring hosp or revascularization), cerebrovascular events (TIA, stroke), heart failure requiring hosp.

LDL was reduced 61% to median of 48 mg/d. these changes were consistent from 4 weeks of therapy until 48 weeks (end of study). also found were non-HDL reduction of 52.0%, apo B of 47.3%, TG of 12.6%, lipoprotein (a) of 25.5%, and HDL increase of 7%.

–rate of cardiovascular events was decreased at 1 year from 2.18% to 0.95% with drug [HR 0.47 (0.28-0.78, p=0.003]. And there was a splaying of the curves at one year, suggesting increasing efficacy of evolucumab over time

–adverse events in 69.2% of evolocumab group and 64.8% of placebo. serious adverse events in 7.5% in each group. No difference in transaminases, CKs. low level of neurocognitive events (<1%), more in the evolucumab group, but, as with the first study, these were not related to the LDL achieved.

So, these articles reveal pretty striking effects of two PCSK9 inhibitors (with remarkably similar changes of 60+% in each study in lipids even after the statin-induced decreases and clinical cardiovascular outcomes decreased by 50+%), though it is important to remember that the clinical efficacy was not a primary outcome, the studies were short-term, and we need longer-term studies both to convince us of efficacy and reveal adverse effects. But, I bring up these articles for a few reasons.

–It is clear that statins either are inadequate or not tolerated in many high-risk patients. reducing PCSK9 activity is the most promising approach I have seen for years, though it would be particularly useful to have an oral and inexpensive medication (how’s that for pie-in-the-sky?). Note that these studies did not look at PCSK9 inhibition as a single agent, just in conjunction with a statin (and it is impressive these PCSK9 inhibitors add so much to statins, given their apparently similar mechanisms of action).

–It is important that there were not many neurocognitive adverse events even with very low LDL levels, since some older studies had found increases in suicides/accidents with lipid lowering, and this was putatively attributed to changes in neuronal cell membrane lipid composition affecting neural signal transmission in the brain. The PCSK9 drugs offer the potential to look at lots of patients with very low LDL levels, and it is reassuring that there were not obvious issues in these 2 studies.

–The benefit attributed to adding PCSK9​ monoclonal antibodies to statin therapy further reinforces the concept of “treating to an LDL target”, which (as those of you who have seen these blogs over time) I really support, despite the 2013 Am Heart Assn guidelines. (I might also add that the 2015 Am Diabetes Assn also continues with the “treat to target” approach, in contradistinction to the Am Heart Assn!!)

–I also want to reinforce that one needs to be careful in accepting surrogate markers as indicators of clinical efficacy (and the reason I am publishing this blog is that there were clinical endpoints in these studies, even though not the primary goals). Both LDL and HDL represent many different lipoproteins, which happen to migrate during electrophoresis to the arbitrarily-designated high vs low density regions. So, this brings up a few issues:

–there are different LDLs, some small and dense, others fluffier. the small dense ones, in a few studies, are much more atherogenic (approx 3-fold), perhaps related to the fact that they are more oxidizable, and it is the oxidized LDL which is taken up in tissue macrophages to make foam cells (though there is some controversy about this of late, many studies suggest that LDL may really be a surrogate marker for oxidized LDL, raising the possibility that simply making changes in regular LDL may not necessarily translate into changes in clinical events). In fact, every study I’ve seen which has looked at it has found that apolipoprotein B levels correlate much better with cardiac events than LDL, and apoB reflects the small, dense LDL more accurately than the total LDL.) the data on ezetimibe, which does lower LDL reasonably well, are still unclear (it is quite striking and notable that the “blockbuster trial” in the Am Heart Assn meeting of November 2014, finding clinical efficacy of ezetimibe, is still unpublished and undissectable 6 months later…)

–and, there are different HDLs. overall HDL is an important negative risk factor, incorporated into the various risk calculators, with a slew of studies showing cardioprotection (and perhaps even more so in women). but about 10-15% of people have a pro-inflammatory/pro-atherogenic variant (with apolipoprotein C-III). This is important because studies with meds which increase HDL (eg, the cholesteryl ester transfer protein inhibitors, such as torcetrapib) do fantastically well in raising HDL levels but actually may increase cardiovasc events. And, apolipoprotein A levels do correlate better with cardioprotection than total HDL levels.

–So, bottom line: we need good alternatives to statins or drugs that can be used with statins, these studies are encouraging for PCSK9 as a target, but we still need to be careful to make sure that these drugs are clinically effective, are well-tolerated, and affordable.

Primary Care Corner with Geoffrey Modest MD: Sinusitis guidelines

23 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

The Am Acad of Otolaryngology — Head and Neck Surgery just published a clinical practice guideline on adult sinusitis (for exec summary, see Otolaryng Head Neck Surg. 2015, Vol. 152(4) 598–609​)​, updating their 2007 guideline.

General background and definitions:

–Sinusitis is common, affecting 1 in 8 adults in the US and with more than 30 million annual diagnoses

–More than 20% of antibiotics prescribed for adults are for sinusitis (fifth most common diagnosis responsible for antibiotic prescriptions).

–Acute rhinosinusitis (ARS) definition: up to 4 weeks of purulent nasal discharge accompanied by nasal obstruction, facial pain/pressure/fullness, or both:

–purulent nasal discharge is cloudy or colored

–nasal obstruction is reported by patient as obstruction, congestion, blockage, or stuffiness, or may be found on PE

–facial pain/pressure/fullness involves anterior face or periorbital region, and may present as headache which is localized or diffuse

​–Viral rhinosinusitis (VRS): when symptoms of acute rhinosinusitis are present < 10 days and are not worsening

–Acute bacterial rhinosinusitis (ABRS): symptoms of acute rhinosinusitis fail to improve in 10 days beyond the onset of upper respiratory symptoms, or worsen within 10 days after an initial improvement

–Chronic rhinosinusitis (CRS): symptoms last > 12 weeks

​–Recurrent rhinosinusitis: 4 or more annual episodes of acute rhinosinusitis

Recommendations:

–differentiate ABRS from VRS as per the definition above (strong recommendation)

–radiology: not get imaging for ABRS or VRS unless a complication or alternative diagnosis is suspected (eg severe headache, proptosis, cranial nerve palsies, facial swelling)

–symptomatic relief of VRS or ABRS: by analgesics, topical steroids or saline irrigation (optional)

–initial management of uncomplicated ABRS: offer watchful waiting (without antibiotics, but only if there is reasonable assurance that the patient will get antibiotics if the condition fails to improve by 7 days after the ABRS diagnosis or sooner if it worsens), or give antibiotics (recommendation)

–choice of antibiotics: amoxicillin with or without clavulanate is first-line therapy, for 5-10 days (recommendation). Systematic review does not show consistent benefit of longer course

–treatment failure for ABRS: reassess patient to confirm diagnosis, change antibiotics (recommendation). not mention what would be their suggested next drug

–CRS diagnosis: differentiate CRS from recurrent ARS; if CRS, confirm sinonasal inflammation by rhinoscopy, nasal endoscopy, or CT scan (strong recommendation)

–Modifying factors: assess patient with CRS or recurrent ARS for chronic conditions that would modify management: asthma, cystic fibrosis, immunocompromise, ciliary dyskinesia (recommendation)

–allergy and immune functioning testing: optional

–polyps: examine for polyps if CRS, and treat with saline nasal irrigation, topical steroids or both (recommendation)

–don’t give topical or systemic antifungal therapy for CRS

Also, there is a useful patient information sheet (their table 4)

Major changes were:

–an extension of watchful waiting as initial management of ABRS regardless of severity (not just in mild cases, as in prior guideline)

–change in antibiotics recommended from amoxacillin to amoxacillin with or without clavulanate

–addition of asthma as a chronic condition that modifies management for CRS (chronic rhinosinusitis)

–treating nasal polyps as a modifying factor with topical intranasal therapy (saline irrigations, steroids)

So, to me these recommendations seem pretty reasonable. The data on the utility of nasal steroids and/or antibiotics is quite mixed, with some good studies showing no benefit of either. So the move to less aggressive antibiotic therapy seems to be a good one. I have been promoting watchfully waiting for the past couple of years, often giving the patient an antibiotic prescription but suggesting that they take them only if the symptoms don’t improve by 10 days or get worse, and indicating the downside of antibiotics (adverse effects, general effects on microbiome, potential for developing resistant organisms). Not exactly sure what the patients do with the prescriptions, but my sense is that patients are coming here with lower expectations of getting antibiotics for likely viral infections than they used to.

A point of clarification: Acute rhinosinusitis can last up to 4 weeks (with chronic after 12 weeks, and the amorphous “subacute” in between). That being said, most acute rhinosinusitis is only 1-2 weeks. Viral is presumed if the purulent discharge lasts <10 days and is improving over time. Bacterial is presumed if it lasts >10 days or is getting worse. The purpose of watchful waiting is that even their presumptive bacterial rhinosinusitis may still get better over the next week on its own (Because it never really was bacterial, vs. the body handling the bacterium by itself without the assistance of antibiotics).

Primary Care Corner with Geoffrey Modest MD: Too low blood pressure and cognitive decline in elderly

23 Apr, 15 | by EBM

By: Dr. Geoffrey Modest 

An Italian prospective cohort study of elderly patients (>65 yo) with baseline cognitive impairment assessed the association between achieved blood pressure in those who were hypertensive and the rate of cognitive decline (see JAMA Intern Med. 2015;175(4):578-585​).

elderly

Details:

–172 patients followed in 2 outpatient memory clinics, mean age 79, 63.4% female, mean mini-mental status exam (MMSE) baseline score of 22.1 (normal range 0-30, with scores of 21-24 indicating mild cognitive impairment, MCI, and 10-21 indicating moderate impairment). MMSE was assessed again after 9 months.

–baseline: 68.0% had dementia, 32.0% had MCI, and 73.3% had hypertension with 69.8% were on antihypertensive drugs. They also assessed an array of common morbidities (including diabetes, CHF, CAD, CKD) as well as ADLs/IADLs (activities of daily living, instrumental ADLs)

–primary outcome: assess the role of office BP, ambulatory blood pressure monitoring (ABPM), and BP meds in changes in cognitive function and progression of disabilities. Secondary outcome: effect of office and ABPM on adverse events.

–patients in the lowest tertile of daytime systolic blood pressure by ABPM, SBP <=128 mmHg, had greater decrease in MMSE (-2.8) vs those in the intermediate tertile (SBP 129-144, with MMSE -0.7, p=0.002) vs highest tertile (SBP >=145, with MMSE -0.7, p=0.003)

–the association between SBP and MMSE decline was significant only in those on antihypertensive drugs, for both subgroups of those with MCI and dementia.

–in multivariate model (controlling for age, baseline MMSE, vascular comorbidities), interaction between daytime SBP and use of antihypertensives was independently associated with greater cognitive decline, for both MCI and dementia subgroups

–the association between office-based SBP and MMSE change was weaker than the ambulatory SBP, not reaching statistical significance.

–for the secondary outcome: both ADL and IADL decreased, but there was no relationship between any of the blood pressure measurements.

–adverse events were pretty high: 26.2% had at least one fall, 6.8% had syncope, 23.7% were hospitalized. There was a nonsignificant trend for a higher incidence of syncope and hospitalization with decreasing daytime SBP (eg, the rates of syncope went from 10.5% in the lowest SBP tertile to 6.8% in the intermediate to 3.4% in the highest tertile. for hospitalizations, it went from 33.3% to 21.7% to 17.2%).  My guess is that this was too small a study to achieve statistical significance for these outcomes.

So, a few points:

–This was not an RCT, where patients were stratified to different blood pressure goals and cognitive decline was measured. So it is hard to draw firm conclusions. ie, did those with lower achieved SBP have more cognitive decline because those patients had their blood pressure lowered more easily (eg, their vasculature was fundamentally different, leading to lower achieved blood pressure in those having more cognitive decline — and, by the way, there are some data finding that the onset of overt dementia is associated with spontaneous lowering of blood pressure)? And would the same group with more blood pressure lowering/more cognitive decline have had less cognitive decline if they were randomized to higher target blood pressures? One possible model is that more aggressively treating early hypertension is cognitively beneficial; but later on, the vascular changes from long-standing hypertension and its effects on cerebral blood flow autoregulation, endothelial function, etc could lead to impaired cognitive function, especially in the presence of dementia (ie, in the absence of cerebral blood flow autoregulation, lowering the blood pressure leads to more cerebral hypoperfusion and decreased functioning). So, there might be different BP targets in people of the same age group who have normal cognition, MCI, or dementia.

–This study reinforces the utility of ambulatory blood pressure monitoring. I posted many blogs over the past 3-4 years with data showing the superiority of ABPM — for diagnosis (about 30% of those in the mild hypertension range by office-based blood pressure do not have hypertension on ABPM), for cardiovascular clinical outcomes (the correlation between hard clinical cardiovascular endpoints in several studies were only significant for APBM and not for office-based blood pressure), and now this study suggests ABPM is a better predictor of cognitive decline. For more extensive discussion of ABPM, see here​.

–This study also reinforces the significance of the JNC8 targets being increased in elderly to <150/90 (see here for my previous blog on JNC8).

–And, again, I would like to reinforce that in elderly patients postural blood pressure changes should be assessed pretty regularly. Given changes in vasculature as noted above and increases in autonomic neuropathy with aging, it is very common (at least in my practice) to see older patients with even somewhat high SBP but having dramatic BP decline on standing. The immediate concern is falling, but I am also concerned about cardiovascular events (decreased myocardial perfusion) and cerebrovascular effects (hypoperfusion, or more vascular dementia from micro or macro infarcts).

Primary Care Corner with Geoffrey Modest MD: Updated HIV guidelines 2015

17 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

NIH just published the 2015 updated HIV guidelines. For the 11-page summary of recommendations (see here). For full guidelines (all 288 pages) see here.

Brief summary of significant changes below:

 –drug resistance testing: no real changes. But just as a reminder, in the setting of virologic failure,​ the genotype is more accurate if done within 4 weeks of discontinuing prior therapy, before there is a rebound of the suppressed virus  which potentially obscures the genotype of the resistant virus. (But the genotype should be done anyway, even if later than 4 weeks, since you might get useful information). Also do prior to starting meds. Add phenotype if patient likely has complex drug-resistant mutations

–when to start therapy? (also not a change): evidence strongest for CD4 <500, but importance of “treatment as prevention” as a means to decrease viral transmission.

–recommended meds (this is a change): for treatment naive (first four are integrase strand transfer inhibitor –INSTI-based, fifth is protease-inhibitor — PI-based)

–dolutegravir/abacavir/lamivudine — but remember to make sure first that they are HLA-B*5701 negative as with all abacavir regimens –available as a a fixed-dose single-pill combination, should be taken with food

–dolutegravir plus tenofovir/emtricitabine, should be taken with food

–elvitegravir/cobicistat/tenovovir/emtricitabine — but only for patients with pre-antiretroviral creatinine clearance >70 ml/min. Available as a a fixed-dose combination, should be taken with food

–raltegravir/tenofovir/emtricitabine

–darunavir/ritonivir plus tenofovir/emtricitabine, should be taken with food

–efavirenz was bumped off the primary recommended drug list (though it is cheaper and has great long-term efficacy) because of more adverse effects.  Still okay as an alternative. And, no need to change someone doing well and tolerating the drug. Atazanavir was also bumped to the alternative list because of adverse effects (jaundice/hyperbilirubinemia, GI toxicity), neprolithiasis, and a recent trial finding nephrotoxicity similar in degree to tenofovir (and we should not give atazanavir with tenofovir if creat clearance <70 ml/min) . Also atazanavir needs gastric acid to work. I personally have lots of patients on efavirenz-based regimens (reflecting my age, and how long ago most of my patients began therapy), and my experience with atripla is that it works almost universally, accommodation to adverse CNS effects happens the majority of the time, and that it is more forgiving in patients who miss pills than I would have expected (there are even some studies that taking it 5 days/week is okay, though I personally would not recommend that).

 –also, in patients unable to take tenofovir or abacavir, can try darunavir/rinonivir plus raltegravir BID (if viral load <100K) or lopinavir/ritonivir BID plus 3TC (these are 2 regimens in the Alternative category, which have only 2 active drugs)

–immunologic failure (low CD4 count with suppressed viral load): also no change — ie, nothing seems to help — adding meds, changing regimens. Focus on modifiable risk factors for chronic disease (smoking cessation, healthy diet, exercise, treating hypertension/hyperlipidemia)

–monitoring: for first 2 years: viral load every 3-4 months, CD4 every 3-6 months; after first 2 years:  can extend viral load monitoring to every 6 months if patient consistently with suppressed viral load. Also if CD4 >500 and viral load suppressed consistently, do not need to check the CD4. if CD4 is 300-500, can check CD4 every 12 months [I do have had a patient with consistent virologic suppression, whose CD4 plummeted from 450 range to 200-250 range, but, again, there are no good interventions in this setting]

–acute/recent HIV: pretty much the same as with treatment for naive infections above, thought they note that ART treatment can be initiated prior to getting genotype results, using a pharmacologically-enhanced PI (eg darunavir/ritonavir) with 2 NRTIs (eg tenof/emtricit), since resistance to PIs emerge slowly and clinically significant transmitted resistance to PIs is uncommon.

–HIV-infected women: no overall difference from above, but beware of drug interactions with oral contraceptives (consider alternative contraception) and avoid efavirenz-based regimen (probs with pregnancy/birth defects, though recent studies have not found this to be a problem). Some details: problems mostly with PIs and NNRTIs which either increase or decrease hormone levels , with risk of pregnancy (decreased hormone effect) or thromboembolism (increased effect). Injectable depot-medroxyprogesterone seems okay in small studies. There are some great tables in the full guidelines, esp Tables 19 and 20, which review all of the known drug-drug interactions, including hormonal contraceptives

–HIV-2: new section added. Will defer to document (page I-25) other than to note that NNRTIs don’t work and the PIs that work best are: darunavir, lopinavir and saquinavir. The INSTIs (eg dolutegravir) have potent activity. And there are labs (Univ of Washington and NY State dept of health) which do quantitative HIV-2 viral load testing [I had previously posted on how great the Univ of Washington was, esp Geoffrey Gottlieb, in both running the viral load and resistance testing for one of my patients]

–Hep C coinfections: lots of new data, with more coming in daily. Basically, screen all HIV patients for hep C, and treat the hep C regardless of CD4 count. Given pill burden and potential adverse events, in those presenting with hep c and hiv with CD4<200, might be useful to start HIV rx first, then to hep C when patient clearly tolerates the hiv meds. Having hiv does not seem to diminish efficacy of hep C treatment.

So, these guidelines are really great overall. Although HIV treatment has migrated into the ID/HIV specialty realm (it had become a “primary care disease” in the past, when there were fewer qualified specialists to take care of the burgeoning epidemic…), in many ways it is much easier to take care of HIV patients now than in the past (much better drugs, decreased adverse effects, hugely decreased pill burden) and, with the longer life of HIV patients, they need strong primary care support anyway to deal with other chronic diseases (and even treated HIV seems to predispose to cardiovascular disease and perhaps cancer). And there are important easy-to-use services to help interpret genotypes or make sure everything is on track (I call the free HIV consultation service in San Francisco ​pretty often when questions come up, and they have experienced clinicians/pharmacists available pretty much right away — 1-800-933-3413)

 

 

Primary Care Corner with Geoffrey Modest MD: Antibiotics for pneumonia

16 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

A Dutch study looked at 2283 patients with community-acquired pneumonia (CAP) admitted to the hospital but not the ICU during three 4-month periods in 2011-2013, with different antibiotics as the preferred empirical treatment for each period, and with the order of these treatments randomized separately for the different hospitals (N Engl J Med 2015;372:1312-23).

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–Case definition: at least 2 of the clinical criteria (below)

–Clinical criteria: cough, purulent sputum or change in sputum character, temp >38C or <36.1C, lung exam with rales and/or consolidation, WBC >10K or >15% bands, CRP >3x upper limit of normal, dyspnea/tachypnea/hypoxemia, new or increased infiltrate on xray

–Median age of patients 70. 2.5% had received PPSV23 vaccine and about 2% PCV13. 20% had cardiovascular disease, 40% COPD or asthma, 10% other pulmonary diseases, 16% cancer, 18% diabetes. 77% had radiologically confirmed CAP

–Intervention strategies:

–β-lactam: amoxicillin (in 31%), amoxacillin plus clavulanate (in 43%), or 3rd generation cephalosporin (ceftriaxone in 17%)

–β​-lactam/macrolide: penicillin, amoxacillin, amoxacillin plus clavulanate, or 3rd generation cephalosporin, in combination with azithromycin, erythromycin or clarithromycin

–fluoroquinolone: moxifloxacin or levofloxacin

–Primary outcome: all-cause mortality within 90 days of admission; secondary outcomes: time to starting oral treatment, length of hospital stay, minor or major complications in the hospital

–Results:

–microbiology: 15.9% s pneumonia, 6.8% h influenza, 2.1% atypicals (mycoplasma pneumoniae, chlamydia pneumoniae, and legionella species), 2.5% viruses, 65% no pathogen identified.

–most frequent reason for deviation from the β-lactam strategy was perceived need to cover atypicals (8.1%)

–Comparing the strategies of β-lactam, β-lactam-macrolide combo, fluorquinolone, respectively, crude 90-day mortality was  9.0% (59 patients) vs 11.1% (82 patients) vs 8.8% (78  patients) – nonsignificant differences. Also nonsignificant when adjusted for pneumonia severity or if limited to group with xray-confirmed CAP.

–These results suggest noninferiority of the β-lactam strategy, even after controlling for providers’ deviating from the antibiotic strategy by clinical considerations.

–median length of stay 6 days for all strategies

–median time to starting oral therapy in the hospital was 3 days for fluoroquinolones and 4 days for others

— they did do urinary antigen testing for strep pneumoniae and legionella pneumophila. Those with legionella were preferentially given ciprofloxacin or other appropriate antibiotics

​–The pathogens found were similar among the strategy groups, but there was more bacterial resistance in the group on the β-lactam​ strategy. This was not associated with worse clinical outcomes.

Current US guidelines:

–US guidelines (IDSA/ATS –infect disease soc of America/amer thorac soc, 2007): for outpatient treatment

–previously healthy and no use of antimicrobials in past 3 months: macrolide (azithro, clarithro, erythro) OR doxycycline (prefer macrolide)

–presence of comorbidities (chronic heart, lung, liver, renal disease; diabetes; alcoholism; malignancy; asplenia; immunosuppression; or use of antimicrobials in the past 3 months): fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750mg] OR β​-lactam (first line: high-dose amoxicillin, amoxicillin-clarulanate; alternatives: ceftriaxone, cefpodoxime, or cefuroxime) PLUS a macrolide.

–in regions with high rate (>25%) of infection with high-level (MIC>=16) macrolide-resistant s. pneumoniae, consider one of the alternative agents and don’t use a macrolide by itself. [note: the US overall had a resistance rate of 41.15% in 2009 (the UK by contrast, has 4.20%)

Overall, pretty low incidence of atypical CAP infections during this study. Although this was a hospital-based study, it seems that an outpatient strategy, with likely less sick patients, would yield similar results.  A major concern in this study is the remarkably low rate of vaccination (<5% had either of the pneumococcal vaccines). The vast majority of these patients, by age or comorbidities, would qualify for both PPSV23 and PCV13 vaccines, and this is especially important because of the worldwide spread of antibiotic-resistant s. pneumoniae. For example, a 2002 article found that 14-16% of pneumococci were multi-drug resistant (at least 3 classes, including β-lactam, macrolides, tetracyclines, sulfonamides, and chloramphenicol). In terms of atypicals), there was a meta-analysis comparing β-lactam antibiotics vs those active against atypical pathogens, finding that in 18 trial with 6749 patients with non-severe community acquired pneumonia, there was no advantage in using specific antibiotics against atypicals other than those with Legionella (in subgroup analysis), where there was a significantly lower failure rate in those on an antibiotic active against Legionella (RR 0.40, 0.19-0.85), a rare cause of pneumonia in this meta-analysis (only 75 patients in whole sample, or about 1%). In this meta-analysis, there was no difference in cure rates between antibiotics, including those considered ineffective for mycoplasma or chlamydia pneumoniae. (see BMJ. 2005;330(7489):456)​​.

So, what makes sense? First, i think we should be aggressive in vaccinating people against pneumococcal pneumonia, the most common of the bacterial pneumonias. Second, it is impressive that both mycoplasma and chlamydia seem to do okay with β-lactam antibiotics, in both this study and the BMJ meta-analysis. I continue to be very concerned about increasing bacterial resistance. Articles in the past have promoted levofloxacin as the go-to antibiotic for pneumonia. But, of course, that might well lead to unintended consequences. Specifically bacterial resistance both with lung pathogens and others (eg, the increasing resistance of H pylori to antibiotics, exacerbated by the fact that single agents are unable to cure the infection but quite good at causing resistance). Perhaps the safest strategy is to use a macrolide, when resistance levels are low, or doxycycline, as suggested by IDSA/ATS, or to use a β-lactam but make sure the CAP was not from legionella (a very unusual cause), which does do better with a fluorquinolone or macrolide. Based on the above studies, I do find the last strategy appealing, though would be great to have a prospective trial confirming it.

Primary Care Corner with Geoffrey Modest MD: Raise the alcohol tax!

15 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

An article was just published in the Washington Post arguing for an increase in the alcohol tax (see here​).

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They make the following points:

–There has been a remarkable cheapening of alcohol: a 10-drink/day drinker in 1950 had to spend 45% of their disposable income on the alcohol. today it is 3%.

–Taxes have fallen dramatically: in today’s dollars, the federal tax on a shot of 80-proof whiskey was 90 cents in 1951, now it’s 13 cents (7-fold decrease). Beer tax has decreased 5-fold.

–Cigarettes, in contrast, have less political support and have had record high taxes (and significantly decreasing consumption)

There is a voluminous literature finding that increased alcohol prices through state/national taxes decrease alcohol consumption, alcohol-related morbidity and mortality, and alcohol-related harmful social interactions (violent assaults, drunk-driving, sexually-transmitted infections). A few studies have been published looking at the effects of a small alcohol tax increase in Illinois in 2009, where the tax on beer was increased by 4.6 cents/gallon, wine by 66 cents/gallon, and distilled spirits by $4.05/gallon.  In one study researchers looked at the relationship between this tax increase and sexually transmitted infection (STI) morbidity, finding that state-wide rates of gonorrhea decreased 21% (3506 fewer infections) and chlamydia decreased 11% (5844 fewer infections); these decreases were (not surprisingly) highest among 25-29 year olds (see Addiction 2014; 109: 904–912). In a study just published on-line in the Am J Public Health this group also looked at fatal car crashes, finding that the tax increase was associated with a 26% decrease in fatal alcohol-related car crashes (decreased 9.9/month), with a striking 37% decrease in those <30 yo. Similar reductions were found in those with alcohol levels <0.15 grams/dl (-22%) vs higher (-25%), and there was no significant gend​er or race differences. They controlled for weather, traffic law enforcement, safety policies, and compared their results to those of neighboring Wisconsin where there was no tax increase. Of note, alcohol-related car crashes account for 10K deaths and 500K injuries per year in the US.

So, there have been lots of studies in the public health journals showing that taxes lead to lower levels of harmful-substance use and fewer medical and social consequences. Even with the seemingly paltry tax increase in Illinois, there were pretty dramatic decreases in alcohol-related fatal car crashes and STIs. None of this is surprising. There have been very old observations (eg Prohibition in the US, German seizure of alcohol in France in World War II, Gorbachev’s anti-alcohol campaign in Russia) leading to major decreases in liver cirrhosis mortality, typically within 6-12 months. This all highlights the major health improvement attributable to decreasing alcohol consumption. Seems pretty clear that the current trend in effectively decreasing alcohol taxes/cost is wrong-headed, though unfortunately there are powerful political lobbies in the US which will make it difficult to change this…. (oh, wouldn’t it be great if public health concerns had a bit more of a role in determining policy??).​

 

Primary Care Corner with Geoffrey Modest MD: H. pylori rescue therapy

15 Apr, 15 | by EBM

By: Dr. Geoffrey Modest 

Most of the cure rates for H. pylori infections are in the 80-90% range, leaving many people with persistent infections.  There have been several articles on rescue therapy, including a recent one with a relatively easy regimen and 90% efficacy (see Aliment Pharmacol Ther 2015; 41: 768–775).  This Spanish/Italian study looked at 200 patients who failed several different initial therapies. details:

–17 hospitals involved in study (15 Spanish, 2 Italian)

–200 patients (mean age 47, 67% women, 13% had ulcers), having had the following prior therapies: 131 patients had  standard PPI-clarithromycin-amoxacillin, 32 with sequential (PPI-amoxacillin x 5 days, then PPI-clarithromycin-metronidazole x 5 days), 37 with quad therapy of PPI-amoxacillin-clarithromycin-metronidazole for 10 days. Failure was defined as a positive 13C-urea breath test 4-8 weeks after therapy.
–all were put on esomeprazole 40mg bid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate 240mg bid for 14 days
–primary outcome: eradication rate confirmed by breath test, as above

–results: 180/200 patients (90%), in intention-to-treat analysis, and 175/192 (91%), on per-protocol anaylsis, had cures. Similar results in Spain and Italy, whether diagnosis was peptic ulcer or dyspepsia, or with the type of prior treatment (eg: success in 88.5% on standard triple therapy, 93.8% on sequential therapy, and 91.9% on quad therapy)
–adverse events in 46% (mostly nausea in 17%, diarrhea in 16%, abdominal pain in 15%, metallic taste in 15%), but these were time-limited to the 14 days of treatment and only 6 (3%) felt the adverse effects were “intense”, though none were considered serious.

So, why did this therapy work so well?

–The role of bismuth is likely a major part: bismuth is not itself associated with bacterial resistance, is synergistic with antibiotics, overcomes clarithromycin and levofloxacin resistance, and has efficacy in setting of metronidazole resistance. Purported additional mechanisms of action: decreases mucin viscosity, binds to toxins produced by h pylori, is adherent to gastric epithelium and prevents bacterial colonization, and reduces the bacterial load.

–Although H pylori resistance to fluoroquinolones is increasing (up to 24% in Europe and 13% in Spain), other studies have found that the addition of bismuth dramatically increased eradication rates to a regimen of PPI, amoxacillin, and levofloxacin for 14 days, finding no difference when the h pylori was sensitive to levofloxacin (85%), but when levofloxacin-resistance was present, adding bismuth increased eradication from 37% to 71%.

–The longer 14-day regimen, which has been found in several studies to improve eradication rates

–The use of high dose esomeprazole. ??the role of the high dosage of 40mg (some studies have found 6-10% higher cure rates with higher doses of PPI).  ??the role of the newer PPI (some data that esomeprazole and rabeprazole are better than the first-generation PPIs)

So, this was a large study of patients with documented primary treatment failure and very high response rates to a 14-day course of quadruple-therapy containing bismuth. Although there were no data presented on resistance patterns of the h pylori, it seems very likely that there were many resistant bacteria (given prevailing resistance patterns). Unfortunately, ​in the US we have very little data (none I can find in Boston), where h pylori is basically an imported infection from many different parts of the world with differing resistance patterns. Clinically, i have had good success with the sequential therapy noted above. But this bismuth therapy seems to be a good one for treatment failure. Although it makes sense to use the regimen they prescribe above in order to get their results, I would opt for high dose pantoprazole or omeprazole, given the difficulty in getting esomeprazole through insurance.

Primary Care Corner with Geoffrey Modest MD: Hypertension goal in people with CAD

14 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

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A new consensus scientific statement was released on the treatment of hypertension in patients with coronary artery disease (CAD) from the Am Heart Assn, Am Coll of Cardiol and Am Society of Hypertension, dealing with the appropriate hypertension target, whether there are benefits attributable to specific classes of anti-hypertensive meds, whether there are different efficacies of different meds in secondary prevention of CAD,  and whether different types of meds should be used in patients with stable angina, acute coronary syndromes, or those with heart failure (HF) — see DOI: 10.1161/HYP.0000000000000018.

Background:

–Hypertension is prevalent: about 1/4 of US adult population (65 million people), and there is an increasing incidence with age (about 1/2 of those >65yo)

–Hypertension is bad for you: a major cardiovascular risk factor (increase of BP by 20/10 doubles the risk of fatal coronary event) and is the major risk factor for stroke (linear increase in risk, beginning at low levels of systolic and diastolic pressures, or SBP and DBP)

–Treatment works: lowering BP leads to rapid reductions in cardiovascular risk (10mm dec in SBP or 5 mm dec in DBP is associated with a 50-60% dec in risk of stroke death and 40-50% dec in CAD or other vascular deaths)

–Hypertension should be seen as part of CAD risk: there is a strong interaction between hypertension and the other cardiovascular risk factors, and the risk attributable to hypertension for CAD is much greater in people who have other additional risk factors (ie, we should not view hypertension as an isolated issue but as part of a complex interplay of risk factors, and we should be more aggressive in hypertension control in the presence of other risk factors)

–The document above is looking at hypertension control alone and by medications, but they do note (very appropriately) that the issues of lifestyle (diet, exercise, weight) as well as management of the other risk factors are very important

Prevention of CAD events in hypertensive patients with CAD

–Lowering BP is more important than using any particular drug, though some combinations are better than others: do not use ACE plus ARB; do use RAAS blockers with thiazides or with CCBs, combinations which have documented  clinical benefit (ACE=ace-inhibitors, ARB=angiotensin receptor blocker, RAAS=renin-angiotensin-aldosterone system, CCB=calcium-channel blocker)

–A few comments about the individual agents:

–b-blockers are useful in setting of concommitant angina, those who had MI (though I should add, the data for benefit are only for the first 2-3 years post-MI), and those with HF (esp carvedilol, metoprolol, bisoprolol)

–ACE/ARBs: esp in those post-MI, or with HF, chr kidney disease (CKD), stroke, CAD (esp if high risk CAD).

​–aldosterone antagonists: esp with HF

–CCB: alternative to b-blockers for those with angina, but may not prevent HF as well as ACE/ARB

BP goals in patients with CAD

–They note that there are considerable holes in the data on BP goal for people with CAD, so precise goals are hard to determine accurately

–There are significantly impaired hemodynamics in the setting of CAD. patients with normal coronaries can sustain lower DBP (myocardia perfusion happens during diastole) because of coronary artery autoregulation leading to increased blood flow; but, CAD impairs this autoregulation. as does LVH and microangiopathy. There are not a lot of human data on this, but the animal data suggests that we be very careful in lowering DBP too quickly or too much. studies mostly confirm that DBP in the 70-79 range are safe. This paper suggests “caution is advised in inducing decreases in DBP to <60 mm Hg”.

–At this point, <140/90 is considered a reasonable target for the secondary prevention of CAD events in those with htn and CAD

–A target of <130/80 may be appropriate in “some people” (not defined) with CAD, previous MI, stroke/TIA, other atherosclerotic disease

–In those with elevated DBP and CAD with evidence of myocardial ischemia, lower the BP slowly, trying to avoid DBP<60 if patient has diabetes or is >60 yo. One very common issue they comment on is that of people (esp older ones) who have stiff aortas, wide pulse pressures, and the imperative to lower the systolic to 150 may lead to a very low diastolic. Based on no direct data, they suggest a “reasonable BP target of <150/80” in those >80 yo. Those who do have DBP <60, should have careful assessment for signs/symptoms of myocardial ischemia. And these patients should be checked for orthostatic changes with standing, avoiding SBP<130, DBP<65 (they comment on this in their section on ischemic HF, but I think this is generally applicable)

HTN management in patients with CAD and stable angina

–First drug is b-blockers. can add CCB (or use this primarily in those not tolerant of b-blocker) and long-acting nitrate as needed to treat angina if symptoms persist on b-blockers. (avoid verapamil/diltiazem in combo with b-blocker because of increased nodal effects)

–Optimal overall treatment is b-blocker if prior history of MI; ACE/ARB if prior MI, LV systolic dysfunction, diabetes, CKD;  and thiazide or thiazide-like diuretic.

​–Target for patients with stable angina is same as in general patients with CAD, as above.

HTN management in patients with ischemic HF

–The usual management for those with reduced EF: thiazides (or loop diuretics if eGFR<30 or severe HF), ACE/ARB, b-blocker (carvedilol, metoprolol, pisoprolol or nebivolol), aldosterone antagonists. consider hydralazine/isosorbide in African-American patients and NYHA class III or IV HF. Avoid nondihydropyridine CCBs (verapamil, diltiazem), clonidine, hydralazine without a nitrate. also try to avoid NSAIDs

–For those with preserved EF: b-blockers, ACE,/ARB, or CCBs.

HTN management in the setting of ACS (acute coronary syndrome).  I will not comment much on this (given my outpatient/primary care focus) other than to say that they reiterate the usual management, but comment that the target BP is <140/90 if patients are hemodynamically stable, though a discharge BP <130/80 is a reasonable option.

One issue not addressed in this document is that people with CAD or HF often need many of the agents above to treat their cardiac symptoms (angina, HF, etc) and their resulting blood pressure is often a lot lower than the 140/90 or even 130/80 target. they do not comment, but, more often than not, I find it necessary to lower the blood pressure significantly more than their target. But, I think it is important to go slowly, check for symptoms and signs of orthostasis, and be especially careful in hot weather (people can get dehydrated and more hypotensive), if there are reported falls, or if GI illness. One remarkable feature of the writing committee is that 15 of the 19 members had NO drug company affiliations…

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