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Dr. Geoffrey Modest is a community-based physician who has worked in a multicultural community in Boston for the past 40 years, where he sees patients regularly and teaches medical residents. He has the academic title of Clinical Professor of Medicine. He has been writing primary care blogs since 2013. <\/em>To leave comments or view other posts, please visit: Geoffrey Modest Medical Blogs<\/a><\/em><\/p>\n A recent article found that certain antihypertensives were better than others regarding cognitive impairment (see<\/span>\u00a0<\/span>https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8800076\/<\/span><\/a>)<\/span><\/p>\n Details<\/span><\/b>:<\/span><\/p>\n \u2014 a secondary analysis of the SPRINT trial assessed cognitive impairment in those on antihypertensive regimens that stimulated angiotensin II receptors 2 and 4 (ARBs, dihydropyridine calcium channel blockers\u00a0such as amlodipine and nifedipine, and thiazide diuretics) versus those that inhibited these receptors (ACE inhibitors, beta blockers, and non-dihydropyridine calcium channel blockers\u00a0such as diltiazem or verapamil)<\/span><\/p>\n \u2014 8685 participants: 2644 (30%) were exclusively on stimulating meds, 1536 (18%) exclusively on inhibiting meds, and 4505 (52%)\u00a0on\u00a0mixed antihypertensive regimens<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0 \u2014 for details of the SPRINT trial, see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2015\/11\/tighter-blood-pressure-control-sprint.html<\/a>, but basically \u00a0this was a pivotal trial finding that lower blood pressures (attained SBP 121 mmHg vs 136mm Hg) was associated with approx 30% decrease in many cardiovascular outcomes and all-cause mortality (though their methodology was eclectic\/not really reproducible in a real clinical setting: their stated blood pressures probably translated to about 5mmHg higher values in normal clinical settings); and for tthe SPRINT substudy in their elderly\u00a0<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 but, of note, the SPRINT study did not include diabetics or those with history of stroke<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 there was discretion by clinicians on which meds to use to treat the hypertension<\/span><\/p>\n \u2014 visit frequency was every 3 months for the duration of the trial<\/span><\/p>\n \u2014 mean age 68, 64% male, 11% Hispanic\/30% non-Hispanic black\/57% of non-Hispanic white<\/span><\/p>\n \u2014 follow-up 4.8 years (the SPRINT trial\u00a0itself\u00a0stopped\u00a0early because of evident\u00a0early\u00a0benefit of many outcomes in those with tighter BP control, but there was an extended followup visit 2-3 years later<\/span><\/p>\n \u2014 confounding was assessed at baseline and was statistically minimized by propensity scoring<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 they matched for age, sex, race\/ethnicity, history of CVD\u00a0or\u00a0CKD, BMI, number of antihypertensive meds classes, SBP tertile,\u00a0and treatment group\u00a0in the study<\/span><\/p>\n \u2014 main outcome of this study: a composite of adjudicated amnestic mild cognitive impairment (MCI) or probable dementia<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 mild cognitive impairment (MCI): noticeable symptoms but not interfering with everyday activities<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 amnestic MCI: memory\u00a0that\u00a0is significantly impaired but other cognitive functions are spared:\u00a0eg language, visual-spatial skills, executive functioning (ie\u00a0capacity to plan ahead, display self-control, follow multiple-step directions, stay focused despite distractions). Amnesic MCI seems to have a higher risk of progressing to Alzheimers and a higher mortality risk<\/span><\/p>\n Results<\/span><\/b>:<\/span><\/p>\n \u2014 amnestic MCI or probable dementia incidence, comparing stimulating versus inhibiting meds:<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 428 events (45 events per 1000 person-years) versus 355 events (59 events per 1000 patient years): risk reduction of 24%, HR 0.76 (0.66-0.87)<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 overall a 25% to 35% decreased risk for the array of unadjusted and several different adjusted models<\/span><\/p>\n \u2014 amnestic MCI\u00a0alone, comparing stimulating only versus inhibiting only users:<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014\u00a0\u00a0373 events (40\u00a0events per 1000 person-years)\u00a0versus\u00a0312 events (54\u00a0events\u00a0per 1000 person-years): risk reduction 26%, HR 0.74 (0.64-0.87)<\/span><\/p>\n \u2014 probable dementia\u00a0alone: 8 versus 10 cases per\u00a01000\u00a0person-years: HR 0.80 (0.57 1.14), not statistically significant\u00a0[but small numbers of people]<\/span><\/p>\n \u00a0<\/span><\/p>\n Their figure showing that after about 1.5 years there was an impressive\u00a0splaying of the curves, showing benefit for those on the stimulating hypertension meds:<\/span><\/p>\n \u2014 subgroup analyses for the combination of probable dementia or amnestic mild cognitive impairment, comparing stimulating to inhibiting antihypertensive users:<\/span><\/p>\n \u00a0\u00a0 \u00a0\u2014 by age groups:<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 <75yo: 3026 patients, 232 versus 168 events, 20% decrease, HR 0.80 (0.65-0.99)<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 >75yo: 1123 patients, 196 versus 187 events, 23% decrease, HR 0.33 (0.63-0.93)<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 females had a 33% decrease, and\u00a0males\u00a0a 20% decrease<\/span><\/p>\n \u00a0<\/span><\/p>\n \u2014 negative control outcome analysis suggested\u00a0the\u00a0presence of residual confounding (by\u00a0assessing some outcomes felt to be very unlikely to be causally related to antihypertensive use):<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2013comparing patients only on stimulating vs inhibiting\u00a0antihypertension\u00a0meds:<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 infectious negative control outcomes: 90 patients (12%) versus 77 patients (16%), strong trend favoring stimulating only with HR 0.78 (0.55-1.11)<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014\u00a0orthopedic negative control outcome: 102 patients (13%) versus 77 patients (18%), HR 0.72 (0.52-1.00), statistically significant 28% decrease<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 hematologic negative control outcome: 48 patients (7%) versus 40 patients (9%), HR 0.83 (0.50-1.37), a trend favoring those on stimulating medications only<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014\u00a0there were\u00a0similar findings\u00a0for these 3 negative controls,\u00a0skewed towards the benefit of those on stimulating medications comparing those on mixed regimens (those on\u00a0combinations of inhibiting and stimulating) versus those on inhibiting medications only, though this time the hematologic negative control outcome was the only one that was statistically significant, the other two had very strong trends to being significant<\/span><\/p>\n \u00a0\u00a0\u00a0 \u00a0\u00a0\u00a0\u00a0\u2014 this all raises the possibility that the 2 groups of patients (on stimulating vs inhibiting meds) were different for some reason<\/span>, since there appeared to be possible benefit from the stimulating meds though this is highly unlikely, especially from 3 different negative control outcomes<\/span><\/span><\/p>\n Commentary<\/span><\/b>:<\/span><\/p>\n \u2014\u00a0several studies have found that more intensive BP control\u00a0overall\u00a0is associated with less MCI<\/span><\/p>\n \u2014 and several past observational studies have suggested that blocking types\u00a02 and 4 angiotensin II receptors lowers\u00a0dementia risk; and, for what it\u2019s worth, a slew of animal studies have found similar results<\/span><\/p>\n \u2014 this study, a secondary analysis of\u00a0the\u00a0well\u2013done\u00a0SPRINT\u00a0hypertension study with lots of granular data, did find consistent decreases in amnestic MCI or probable dementia across subgroups by age, sex, race\/ethnicity,\u00a0the presence of cardiovascular\u00a0or\u00a0kidney disease, BMI, number of antihypertensive medication classes, systolic blood pressure, or SPRINT treatment group. And these results were consistent across their various sensitivity analyses with different statistical adjustment strategies<\/span><\/p>\n \u2014 there is an argument in the medical literature that we clinicians should be prescribing ARBs over ACE inhibitors<\/span>\u00a0for hypertension<\/span>:<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0<\/span>\u2014 a real-world effectiveness study found that ARB\u2019s (vs ACE-I\u2019s) should perhaps be the best choice in the treatment of hypertension, given their better safety\u00a0<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 there are real concerns about the half-life of these medications. Other studies have found an increased risk of stroke\u00a0in\u00a0those on ACE inhibitors, which may be attributed to the fact that their effectiveness wears out after 12 to 18 hours and tends not to be effective in the early morning at the time of the cortisol (and hypertension) surge. The increased stroke risk\u00a0was found in 4-5 studies I have seen,\u00a0\u00a0including the ALLHAT study\u00a0(ALLHAT was a community-based study comparing amlodipine to chlorthalidone and lisinopril to chlorthalidone).<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 one drawback of losartan is that it achieves its full 24\u2013hour effectiveness only at its highest dose of 100 mg per day. Other ARBs do have longer half-lives, for example valsartan has a 24\u2013hour effectiveness independent of its dose<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014\u00a0but\u00a0losartan (and\u00a0not other ARBs) have the benefit of lowering serum uric acid levels (it is\u00a0uricosuric) and is even mentioned in the 2012 American Rheumatology Assn guidelines for primary treatment of hyperuricemia, and is included in the 2020 guidelines\u00a0on hyperuricemia\u00a0as a preferred antihypertensive (https:\/\/wchh.onlinelibrary.wiley.com\/doi\/epdf\/10.1002\/psb.1887<\/a>\u00a0)<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014 hyperuricemia itself is associated with increased cardiovascular disease and overall mortality<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 for an interesting evolutionary perspective:\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2019\/04\/uric-acid-lowering-cardiovasc-benefit.html<\/a>\u00a0\u00a0<\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u00a0\u00a0\u00a0\u00a0\u2014 allopurinol seems to decrease cardiac events\u00a0in several studies:\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2016\/03\/hyperuricemia-allopurinol-decreases.html<\/a><\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 \u2014 and another one documenting an increased incidence of cardiac mortality with hyperuricemia, with uric acid threshold over around 5 mg\/dL and increasing\u00a0mortality\u00a0relatively linearly after that:\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2020\/01\/uric-acid-threshold-for-increased-cad.html<\/a><\/span><\/p>\n \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u2014 And, perhaps another small benefit: if a patient has heart failure and would likely benefit from sacubitril\/valsartan (entresto), there is a higher risk of angioedema in those on ACE inhibitors (the ACE should be stopped for 3 days, but that type of patient advice creates<\/span>\u00a0some increased risk of a<\/span>\u00a0potentially very serious error, and that possibility would not need to happen if they were on an ARB). See\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2022\/05\/heart-failure-outpatient-initiation-of.html<\/a><\/span><\/p>\n \u2014 it would also be useful to have a breakdown of the other stimulating antihypertensives: amlodipine is the drug-of-choice for almost all hypertensives per the NICE (UK) guidelines (it has several great features, including a full 24 hour protection, decreasing blood pressure variability,etc: eg see\u00a0https:\/\/gmodestmedblogs.blogspot.com\/2015\/07\/blood-pressure-variability-and-heart.html<\/a>) or chlorthalidone\u00a0https:\/\/gmodestmedblogs.blogspot.com\/2023\/01\/hypertension-hctz-vs-chlorthalidone.html<\/a>\u00a0<\/span><\/p>\n Limitations:<\/strong><\/p>\n \u2014 the SPRINT trial\u00a0excluded patients who were\u00a0diabetic (a large and growing group\u2026) and those with strokes, limiting\u00a0broad\u00a0generalizability\u00a0of their results (and these subsequent analyses)<\/span><\/p>\n \u2014 this extension of the SPRINT trial was after the original trial stopped 2-3 years previously, with a \u201cfinal extended follow-up visit\u201d. Not clear how extensive this visit was and if there were subsequent changes in antihypertensive meds (I suspect this was included) or the array of other medical\/psychosocial variables that might have affected cognition (stress, sleep, depression\u2026), which i suspect were not included<\/span><\/p>\n \u2014 the SPRINT study by design was not one of new med users (eg initiating an ARB vs ACE inhibitor), but one of people mostly \u00a0already on these meds and following them. So, not quite as easy to interpret the results: what\u00a0<\/span>meds\u00a0<\/span>were they on before?\u00a0<\/span>were<\/span>\u00a0they on an ARB because of problem with ACE? Or other issues? Or other covariates? How long were they already on meds that either were stimulating or inhibiting or combos? This would bias the results.<\/span><\/p>\n \u2014 the issue of\u00a0<\/span>residual\u00a0<\/span>confounding is a bit complex. The baseline groups did have different outcomes in the assessment of the 3 very different negative controls of infectious, hematologic and orthopedic diseases.\u00a0<\/span>and<\/span>, the<\/span>ir<\/span>\u00a0clinicians may have chosen different antihypertension meds\u00a0<\/span>for the\u00a0<\/span>\u00a0different patients for a<\/span>n unknown but important<\/span>\u00a0reason, which would inflict a bias on the results \u00a0The researchers did model their analyses by propensity matching, a mathematical approach to equalize the 2 groups. But this may not reflect the real world: see\u00a0http:\/\/gmodestmedblogs.blogspot.com\/2020\/03\/tramadol-fo-oa-inc-mortalityprobs-with.html<\/a>\u00a0.<\/span><\/p>\n \u00a0<\/span><\/p>\n So, given the reasonable interchangeability of ARBs and ACE inhibitors in the treatment of hypertension, but the real-world issue of cough a<\/span>s a<\/span>\u00a0common<\/span>\u00a0adverse effect of ACE inhibitors (with the associated patient anxiety, increased medical visits, perhaps increased chest xrays with their attendant radiation exposure, and now a reasonable likelihood that dementia may be increased<\/span>)<\/span>, it does seem reasonable that an ARB should be\u00a0<\/span>prescribed<\/span>\u00a0vs ACE inhibitor. Of course, the absolute number of people in this SPRINT substudy getting MCI and amnestic MCI is\u00a0<\/span>pretty\u00a0<\/span>small, but:<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014\u00a0<\/span>cognitive impairment is<\/span>\u00a0a pretty terrible thing to get, and clearly has awful consequences for the patient, their self-esteem, their family and community, etc (though it would be interesting to know longer-term followup: is there a higher risk of Alzheimers??? Following the SPRINT cohort for another several years might be helpful to assess the more profound effect of developing moderate to severe dementia<\/span><\/p>\n \u00a0\u00a0\u00a0 \u2014 a small\u00a0<\/span>increased\u00a0<\/span>absolute risk<\/span>\u00a0of MCI<\/span>\u00a0translates into very large numbers of people when these meds are\u00a0<\/span>prescribed to a<\/span>\u00a0huge numbers of people treated for hypertension (about 50% of the US adults have BP >130\/80, 116 million people)<\/span><\/p>\n \u2014 and, by the way, still about 20% of older adults are still prescribe b-blockers as their initial monotherapy in the absence of\u00a0 heart failure or coronary artery disease<\/span><\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":" Dr. Geoffrey Modest is a community-based physician who has worked in a multicultural community in Boston for the past 40 years, where he sees patients regularly and teaches medical residents. He has the academic title of Clinical Professor of Medicine. He has been writing primary care blogs since 2013. To leave comments or view other […]<\/p>\n","protected":false},"author":20392,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[1324],"tags":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/posts\/2794"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/users\/20392"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/comments?post=2794"}],"version-history":[{"count":15,"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/posts\/2794\/revisions"}],"predecessor-version":[{"id":3049,"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/posts\/2794\/revisions\/3049"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/media?parent=2794"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/categories?post=2794"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/gim\/wp-json\/wp\/v2\/tags?post=2794"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
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