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Hypertension

Primary Care Corner with Geoffrey Modest MD: Blood Pressure Guidelines for Older Adults

27 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The American College of Physicians and the American Academy of Family Physicians just published guidelines on the pharmacologic treatment of hypertension in adults over 60 yo, with both a systematic review and meta-analysis (see doi:10.7326/M16-1785), and a clinical practice guideline (see http://annals.org/aim/article/2598413/pharmacologic-treatment-hypertension-adults-aged-60-years-older-higher-versus )

Results:

  • They analyzed 46 publications representing 21 randomized controlled trials and 3 cohort studies
  • 9 trials show that intensive blood pressure treatment substantially improved outcomes in patients with moderate to severe hypertension, with SBP >160 mmHg. The data on lower systolic blood pressures also showed benefit but the results were less consistent.
  • Overall studies of patients achieving SBP <140 mmHg were similar to those that achieved 140, although the reduction in stroke risk was more consistent in the studies where patients achieved the higher SBP
  • In 6 trials comparing different treatment targets with 41,491 patients, treatment targets of SBP <140 mmHg or diastolic blood pressure of <85 mmHg were associated with only marginal benefit, with wide confidence intervals:
    • 14% nonsignificant reduction all-cause mortality, RR 0.86 (0.69-1.06)
    • 21% reduction in stroke, RR 0.79 (0.59-0.99)
    • 18% marginally significant reduction in cardiac events, RR 0.82 (0.64-1.00)
    • Because of their size and the event rates found, these analyses were dominated by the SPRINT and ACCORD trials. SPRINT (which excluded diabetics as well as those with SBP >180, prior stroke, urinary protein excretion >1 g per day or symptomatic heart failure/EF <35%) found marked reductions in mortality in cardiac events, though the ACCORD trial (which included only diabetics, though did achieve an SBP of 119 mmHg, similar to SPRINT) did not find any reduction in mortality or major cardiovascular events with intensive treatment [though other trials found benefit of hypertension treatment to be at least as strong in diabetics]. Also, the SPRINT trial stopped earlier than projected because of benefit, which, as mentioned in my blog on it noted below, will tend to exaggerate benefits and perhaps decrease finding risks.
  • Overall, tighter control “may prevent on average, roughly 10 to 20 events for every 1000 high-risk patients treated over 5 years across a population”
  • Harms of more intensive therapy: in general the evidence was relatively low to moderate strength, but did not find clear evidence of more renal, cognitive impairment, deterioration of quality-of-life/functional status, or increase in fractures or falls, though there was low-quality evidence for increase in syncope.

Recommendations:

  • Initiate treatments in adults over 60 years old who have systolic blood pressure persistently at or above 150 mmHg, to reduce the risk for mortality, stroke, and cardiac events (strong recommendation, high quality evidence).
  • Consider initiating or intensifying pharmacologic therapy in patients over 60 years old with a history of stroke or TIA to achieve a targeted systolic pressure of less than 140 mmHg to reduce the risk of recurrent stroke. (Weak recommendation, moderate quality evidence)
  • Consider initiating or intensifying pharmacologic treatment in some adults greater than 60 years old at high cardiovascular risk to achieve a target systolic pressure of less than 140 mmHg to reduce the risk of stroke and cardiac events. (Weak recommendation, low quality evidence)
  • And for all of these recommendations, the risks and benefits should be periodically discussed with the patient.

Commentary:

  • There are really no studies that include the real elderly. The SPRINT elderly subgroup (those patients over 75 at enrollment), still had a mean age of 80, with SD of only 4 years, so really does not inform my practice with lots of people in the 85-100 age range. one might glean from the above trials that the lower blood pressure may well be better, since there was no evidence that age mattered in the groups analyzed (again, not including the very old), subgroup analyses from SPRINT as well as the HYVET trials found that frailty did not matter, and there was more absolute benefit in those with higher cardiovascular risk (and age plays into that). But, at least my practice in the elderly and especially in the very old is to check orthostatics regularly (looking for both initial and standard orthostatic hypotension: See http://blogs.bmj.com/ebm/2016/05/20/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension-revisited/for details), try to get home-based BP measurements (and preferentially use these to guide therapy, as long as I have confirmed that the patient measures blood pressure accurately and the cuff is accurate), and assess cognitive function more aggressively (see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/ which is an Italian prospective study in patients mean age of 79 with some baseline cognitive impairment, finding that those in the lowest BP group (SBP<128 mmHg) had more cognitive decline than those with higher pressures)​. So, my guess (without data) is that the benefits will persist in the very old, though I suspect the harms will be greater (patients more frail, more comorbidities, and more sensitive to meds)
  • My major concern with these articles on tighter blood pressure control in general is that there is a tendency in clinical practice to attempt to achieve the goal blood pressure they achieved in the study. However, this brings up a few issues:
    • In general the studies have very specific ways that they measured the blood pressure. The general real-world approach, at least in my experience, is to have a medical assistant bring the patient into the room and measure the blood pressure/record it in the electronic medical record. I have consistently been measuring manual blood pressures myself for the past many years, typically with the patient sitting on the exam table and resting a few minutes while I write my notes in the other room, and often find striking differences from the recorded blood pressure, not uncommonly 30 to 40 mmHg difference. Although most often my recording is much less than that of the medical assistance, at times it is much more (the 118/68, which really is 190/110!!!). So in general I am concerned about relying on automated blood pressure recordings (which in general is less reliable in people with atrial fibrillation and arrhythmias, as well), though my main concern is that the patients, perhaps somewhat deconditioned, walk into the room and sit down without resting and have largely unreliable readings.
    • For example, in the SPRINT study, which did achieve lower blood pressure in the tight control group than often found in other trials (123/62, in the elderly subgroup), they measured the blood pressure as follows: the staff person would tell a patient that they needed to rest for 5 minutes before taking the blood pressure, would leave the room completely, would return but not speak a word with the patient and immediately take the blood pressure. Argument has been raised in the literature that the blood pressure measured in randomized controlled trials is typically 5 to 10 mmHg lower than the clinic-based blood pressure (i.e. a randomized trial with an achieved systolic blood pressure of 123, as above, may be equivalent to a clinic-based blood pressure of 130 or so). For details of the SPRINT trial, see http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/, which reviews the results of the overall trial, as well as http://blogs.bmj.com/ebm/2016/06/02/primary-care-corner-with-geoffrey-modest-md-sprint-trial-elderly-subgroup-study-of-lower-blood-pressure-goal/ which looked at the predesignated subgroup of those greater than 75 years old).
    • There are also significant questions as to the general reliability of office-based blood pressure, both because of whitecoat hypertension as well as masked hypertension (see http://blogs.bmj.com/ebm/2016/12/12/primary-care-corner-with-geoffrey-modest-md-masked-hypertension/ , as well as the frequent observation that ambulatory blood pressure monitoring is much more predictive of clinical events, leading to the USPSTF and other international groups suggesting this is the preferred mechanism to diagnose hypertension (see http://blogs.bmj.com/ebm/2015/01/15/primary-care-corner-with-geoffrey-modest-md-uspstf-recs-on-ambulatory-blood-pressure-monitoring/
  • So, my real concern is that we may be basing important clinical decisions based on inaccurate data, and that we may be significantly over-treating (predominately) or under-treating hypertension, with their attendant potential adverse outcomes​

By the way, there was a review of intensive lowering of blood pressure in the elderly (defined as >65 yo), essentially simultaneous with the above, in the Journal of the American College of Cardiology, which identified only 4 studies (all included above) with 10,857 patients that met their criteria, finding that intensive blood pressure control with SBP <140 lead to a significant decrease in major cardiovascular events, including cardiovascular mortality and heart failure, but no difference in stroke or MI (see DOI: 10.1016/j.jacc.2016.10.077​). This exemplifies one of the points I made in my blog http://blogs.bmj.com/ebm/2016/11/21/primary-care-with-geoffrey-modest-md-lessons-ive-learned-from-looking-at-the-medical-literature/ , that systematic reviews and meta-analyses may well come to different conclusions based on their own inclusion and exclusion criteria, and that we in the trenches (who are responsible for reading and considering implementing important changes in clinical practice) really need to assess how those authors configured their analyses and the relevance of their conclusions to our clinical practice. Not a simple feat.

Primary Care Corner with Geoffrey Modest MD: Masked Hypertension

12 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent study compared clinic blood pressure (CBP) measurements and ambulatory blood pressure monitoring (ABP), finding much more masked hypertension than white-coat hypertension (see doi.org/10.1161/CIRCULATIONAHA.116.023404). White-coat hypertension is when the CBP is higher than the ABP; masked hypertension is the opposite.

Details:

  • 888 healthy, employed, middle-aged individuals not on antihypertensive medications, found in a workplace screening program to have a blood pressure of <160/105 mmHg, then had 24 hour ABP.
  • Mean age 45, 89% female, 7.4% black/12% Hispanic
  • They compared the awake ABP (aABP), the CBP, and the difference. CBP was an average of nine readings over three visits after being seated a minimum of five minutes, and the participants had not smoked, eaten or had caffeinated beverages in the prior 30 minutes. Two other blood pressures were recorded 1 to 2 minutes afterwards. Those with CBP >140/90 were defined as having clinic-based hypertension, those with aABP >135/85 were defined as hypertensive. Those with elevated CBP but nonelevated aABP were defined as whitecoat hypertension. Those with nonelevated CBP but elevated aABP were classified as having masked hypertension.

Results:

  • Average systolic/diastolic aABP was 123/77 mmHg
  • Average CBP was 116/75 mmHg => average CBP was 7/2 mmHg lower than aABP
  • 3% were hypertensive by CBP; 19.2% were hypertensive by aABP; 15.7% with nonelevated CBP had masked hypertension. specifically,
    • For those with clinic blood pressure higher than ambulatory (white-coat), found overall in 17.8% by systolic pressure and 35.8% by diastolic:
      • Difference of > 5mmHg: 6.9% of subjects by systolic, 14.2% by diastolic
      • Difference of >10 mmHg: 2.5% systolic, 4.2% diastolic
      • Difference of >15 mmHg: 1.1% systolic, 0.9% diastolic
    • For those with ambulatory blood pressure higher than clinic blood pressure (masked), 82.2% of systolic and 64.2% diastolic
      • Difference of >5 mmHg: 63.7% systolic, 32.4% diastolic
      • Difference of >10 mmHg: 34.8% systolic, 9.2% diastolic
      • Difference of >15 mmHg: 14.4% systolic, 1.7% diastolic
    • This difference was most pronounced in young adults and those with normal BMI, decreasing at older ages and higher BMIs but did not disappear
    • No difference between men and women, black patients vs nonblack, Hispanic vs non-Hispanic, cigarette smokers vs past smokers vs nonsmokers

Commentary:

  • I had seen a few studies on masked hypertension with similar findings, but I must admit I assumed there was lots of hyperbole/biases to their conclusions, that white coat hypertension was undoubtedly much more common than masked hypertension. But — just goes to show you: for several patients their daily lives are even more stressful than the calm and relaxing clinician’s office….
  • This is clearly a flawed study in terms of drawing generalizable conclusions:
    • CBP was not really checked in a “clinic”, but at a workplace
    • As a workplace-based study, there is the “healthy worker bias” which not only selects people who tend to be healthier, but also selects people who may have somewhat higher social economic status (which itself seems to confer better health outcomes), as well as having few individuals over the age of 65. Of note only 5% of these people had elevated CBP, likely reflecting this healthier population.
    • The study did not include many nonwhite patients.
  • These biases clearly undercut the generalizability of the study’s results. Also, the high level of masked hypertension raises the question that more fit people (lower BMI) exercise more and have higher ambulatory pressures.
  • BUT, other studies have found masked hypertension in a wide array of patients (see Bobrie G. J Hypertension 2008, 26:1715) which found that the prevalence of masked hypertension was between 8 and 20%, and as high as 50% in treated hypertensive patients. A few studies mentioned in this meta-analysis found that masked hypertension was actually associated with 2 to 3 times the cardiovascular events than either white-coat hypertension or controlled hypertension in treated patients. In untreated patients, the data seems pretty mixed: studies varied between no increased cardiovascular risk to the same risk as untreated sustained hypertension. a couple of the studies:
    • The Jackson Heart Study (Diaz KM. American Journal of Hypertension 28(7) July 2015) looked specifically at African-Americans, finding that the prevalence of masked hypertension was 25.9% (34.4% in people with normal CBP) and that all of the surrogate markers of carotid artery intima-media thickening, left ventricular mass, and microalbuminuria were elevated (vs controls) in those with masked hypertension, and similar to those with sustained hypertension. They also found that male gender, smoking, diabetes, and antihypertensive medication use were independently associated with masked hypertension.
    • And, another study, the Dallas Heart Study (Tientcheu D. JACC. 2015; 66: 2170) assessed masked versus whitecoat hypertension and sustained hypertension in a group with 54% being African-American. They found a 17.8% prevalence of masked hypertension and a 3.3% of whitecoat hypertension. The risk for cardiovascular events over nine years was significantly higher in both the masked hypertension and sustained hypertension groups, but was barely significant in the whitecoat hypertension group, assessing cardiovascular outcomes. Controlling for an array of risk factors including clinic blood pressure measurements, they found that higher 24-hour ambulatory systolic and diastolic pressures were independent risk factors for new cardiovascular events. The adjusted relative risk for cardiovascular events was a 34% increase for each 1-SD increase in the 24 hour blood pressure, a 30% increase for ambulatory systolic blood pressure during the daytime and a 27% increase for ambulatory systolic blood pressure during the nighttime. For diastolic pressure the cardiovascular risk was 21% for each 1-SD increase for each, 24% for ambulatory diastolic pressure during the daytime and 18% for the nighttime. This graphs shows that there was essentially no relationship between clinic systolic pressures and cardiovascular events, that the correlation within each group of office-based blood systolics was only by ABP.

photo

  • So, there are a number of questions that arise from these studies:
    • There is no clear consensus on how to define masked hypertension/what are the cutpoints? They used an ABP cutpoint of 135/85 mmHg as their definition of hypertension.  A consensus guideline suggested a 24-h average of >130/80, a daytime average of >135/85, and a night-time average of >120/70 (see O’Brien E. Hypertension 2013; 62: 988)
    • Are the clinical effects of masked hypertension really just those of increased blood pressure variability (see http://blogs.bmj.com/ebm/2016/10/04/primary-care-corner-with-geoffrey-modest-md-blood-pressure-variability-increases-cardiovasc-disease/)?
    • Is there any real clinical advantage to identifying and treating patients with masked hypertension, and how?
    • How do we look practically for masked hypertension in our patients given that they have normal blood pressure in the office (assuming the studies suggest that identifying and treating these patients actually matters).

So, why, you might ask, am I bringing up masked hypertension, when there are no studies showing that unmasking it and treating it does anything???

  • I think it is always useful to hear about different information/perspectives which challenge the predominant ideology. The early studies on “mild hypertension” focused exclusively on clinic-based diastolic blood pressure. Then a few epidemiologic studies documented that systolic blood pressure was an even better predictor of cardiovascular events, moving the clinical target pressures into clinic-based full blood pressures. Then several studies either supporting or debunking the role of white-coat hypertension as important, and now, per my reading, suggesting that it is a little important but much less so than the other forms of hypertension. Then lots of studies on ambulatory blood pressure finding it to be much more predictive of clinical events than clinic-based blood pressure, and other studies showing that blood-pressure variability (either from clinic visit to clinic visit, or over the course of a 24-hour period) as being important. Now, over the past few years, emerges masked hypertension. We still do not know what to do with this, but there are a constellation of studies suggesting that this may be as important as sustained hypertension. But I think the real positive of this evolution in our thinking is that we are now situating hypertension in the realm of a person’s actual life instead of the artificial constructs of the clinic setting, and the data support this…
  • Masked hypertension fits in well with the increasing data on ABP as the predictor-of-choice for clinical events
  • It probably makes sense to think about masked hypertension in certain people, esp those with highish clinical blood pressure, since as in the above study, they are more liklely to have masked hypertension. Or in those with possible hypertension-related damage (e.g. retinal changes, LVH, renal dysfunction/microalbuminuria….) And, I think it makes sense to use the diagnosis of masked hypertension to reinforce the generally-useful-anyway lifestyle changes (diet, exercise, stress reduction…). I would be hesitant to prescribe meds for masked hypertension, lacking any real data on outcomes
  • And, as to how to measure it, it would be great to have ABP monitoring available and inexpensive. But, my completely untested hypothesis (though likely more practicable) is to use home-based or pharmacy-based measurements (which seems to be more accurate than CBP and approach that of ABP in the few studies done), with the clear prescription that the person should sit down/relax for several minutes, then check the numbers.

And, for the complete set of hypertension blogs, see http://blogs.bmj.com/ebm/category/hypertension/

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: HTN Goal in Diabetics without CVD

7 Nov, 16 | by EBM

By Dr. Geoffrey Modest

A large Swedish population study found that in diabetics with no previous cardiovascular disease, there were progressively fewer cardiovascular events as the systolic blood pressure was lower (see doi.org/10.1136/bmj.i4070).

Details:

  • 187,106 patients in the Swedish national diabetes register for at least 1 year, <= 75 yo, and no known cardiovascular disease (CVD), from 2006-2012 with mean follow-up of 5.0 years. From 861 primary care units and hospital outpatient clinics
  • Most of the demographics got worse as the cohort in each 10-mm group of BP increased: median age was 55 in the lowest SBP group vs 64 in the highest; duration of diabetes 4.8 vs 6.8 years and the higher SBP group was more likely to be on more aggressive diabetes management;  LDL 2.8 vs 3.0 mmol/L but HDL 1.3 in all; more micro/macroalbuminuria in those with the highest SBP; and the mean number of BP meds was 0.7 in the SBP 110-19 cohort vs 1.1 in the 130-139 cohort vs 1.6 in the >160 mmHg cohort

Results:

  • ComparingSBP 110-119 mmHg vs those with SBP 130-199:
    • Non-fatal MI, RR 0.76 (0.64-0.91, p=0.003), 24% risk reduction
    • Total acute MI, RR 0.85 (0.72-0.99, p=0.04), 15% risk reduction
    • Non-fatal CVD, RR 0.82 (0.72-0.93, p=0.04), 18% risk reduction
    • Non-fatal coronary heart disease, , RR 0.88 (0.79-0.99, p=0.04),12% risk reduction
    • There was no suggestion of J-shaped relationship, except for heart failure and total mortality, and this was only significant for the lowest SBP group
  • Figure below shows that there was a consistent relationship between SBP and non-fatal CVD events over the course of the study. For all of the CVD endpoints, this relationship held, even after controlling for age, sex, duration of diabetes, type of diabetes treatment, HbA1c, smoking status, LDL, HDL, triglycerides, micro/macroalbuminura; as well as thiazide diuretics, loop diuretics, calcium antagonists, spironolactone, b-blockers, and drugs for heart disease. Of note, they did not control for those on vs not on antihypertensives, which may be important.

photo

 

Commentary:

  • So, why is it so difficult to zero-in on a goal blood pressure in diabetics? This study suggests that lower blood pressure is better. But the various guideline groups have been increasing the BP goal lately, though based on no new evidence: the ADA (Am Diabetes Assn) in 2016 set the overall BP guidelines at the higher level of <140/90 (see http://blogs.bmj.com/ebm/2016/03/09/primary-care-corner-with-geoffrey-modest-md-new-diabetes-guidelines-from-ada/) and explicitly did not recommend it to be <130/70 in older adults, in conformity with JNC8 (which also has a higher goal than JNC7)
  • I think there could be various different explanations:
    • The current study focused on a less-sick population than most of the others: a younger cohort, who had no known baseline CVD, and some did not have treated hypertension
      • Is the diabetes itself different? (perhaps longer-standing diabetes creates end-organ changes which dictate different optimal BP goals)
      • Are we using diabetic medications which make things worse, and using more of them on patients with longer-standing and more treatment-resistant diabetes? Similarly with the antihypertensives?
        • In terms of diabetes control, a case in point here is the ACCORD trial, one of the major studies heralded as a reason to raise the target A1c. Those assigned to the “intensive control wing”, achieved an A1c of 6.4, but 91% were on a thiazolidinedione (TZD), vs an A1c of 7.5 in the less aggressively treated group but with 58% on a TZD. But the TZD of choice was rosiglitazone, which has the unfortunate tendency to increase cardiovascular outcomes (and is one of the reasons that I find it unfortunate that the FDA and most of us accept A1c as an acceptable clinical surrogate).
        • And, this brings up the issue of medication-flogging…. are those patients with easy-to-control diabetes or hypertension different? As in the first point, is there a fundamental difference in their pathophysiology or clinical outcome? A subgroup analysis of this ACCORD study actually found that those who achieved a lower A1c in fact did better, all the way down to an A1c of 6!!, but as the number of meds needed in the attempt to lower the A1c increased, they had worse outcomes (i.e., medication-flogging of patients to improve their A1c led to worse outcomes even at a much higher A1c). See Riddle MC. Diabetes Care; 33:983. An Italian observational study also found that the goal of A1c in terms of clinical outcomes was lower in those with fewer chronic medical conditions (see Greenfield S. Ann of Intern Med 2009; 151: 854).
        • This last point brings up the parallel issue: should the blood pressure goal be different in those with fewer chronic changes from long-standing hypertension (e.g. atherosclerosis, or changes in the local autoregulation of blood pressure at a microvascular level) vs those with perhaps newer onset hypertension with fewer of these changes? should we have different BP goals in those who easily achieve a blood pressure of 110-120 systolic if it can be achieved with 1-2 drugs, vs those with SBP of 140+ systolic, who would be struggling to achieve even close to the lower range with 4 drugs? It was certainly the case in the Swedish study that as the SBP of the cohort increased, there were more meds being used, distributed pretty evenly amongst the different types of meds.
        • The prior observational studies have often found a J-shaped relationship between blood pressure and CVD events in diabetics, though this has been questioned by the potential bias in observational studies that patients who had more bad outcomes at lower pressures did so because they were really sick at the start, and it was this increased morbidity that led to lower blood pressure. It is notable in the above Swedish study that the J-shaped curve did happen in those with lower blood pressure, but only for total mortality and heart failure, and not for the specific CVD outcomes, suggesting that there may have been issues that these patients with lower SBP were indeed sicker. In fact those who died in this Swedish study were likely to have had more comorbidities, since they had higher rates of smoking (32%), use of loop diuretics, spironolactone, and drugs for heart disease.
        • The ACCORD-BP study of diabetic patients (N Engl J Med 2010; 362: 1575), another wing of the above ACCORD study, found no overall benefit in 4733 patients in those achieving a systolic BP of 119 mm Hg vs 133.5 mm Hg, except for the prespecified secondary outcome of stroke, where there was a 41% decrease (p=0.01), but at the expense of an increase in serious adverse events (from 1.3% of the population to 3.3%). The absolute risk of stroke was 0.53%/yr vs 0.32%/yr, which translates roughly to 2.6% vs 1.6% over the 4.7 year study. The serious adverse events were largely hypotension/syncope/bradycardia or arrhythmia/hyperkalemia. The intensive group averaged 3.4 BP meds and the standard group 2.2. But, as opposed to many strokes, all of these serious adverse could be tracked and corrected, and there was no evidence of increased morbidity/mortality from these adverse events. Other trials, such as ONTARGET found a J-shaped curve, and the INVEST trial found no benefit if the SBP were lowered below 130, (though a subgroup analysis of ONTARGET found that it was those with a higher baseline risk who had CVD events, rather than the degree of reduction of the BP). These are the trials cited in JNC8 and the ADA guidelines as the reason to shoot for a higher SBP target.
      • So, my best guess is that lower SBP is better for those who don’t have lots of comorbidities and do have more easily treated hypertension, with the following caveats:

Also, http://blogs.bmj.com/ebm/2015/03/06/primary-care-corner-with-geoffrey-modest-md-blood-pressure-goals-in-diabetics/, a recent meta-analysis found benefit of a goal SBP of around 130 to be better overall than 140.

 

Primary Care Corner with Geoffrey Modest MD: Lower Blood Pressure in Elderly and Decreased Morbidity

20 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent study of older community-dwelling high-risk hypertensive patients looked at the relationship between their achieved blood pressure and cardiovascular outcomes (see Myers MG Hypertension. 2016;68:866).

Details:

  • 6183 community-dwelling Ontario residents >65yo on antihypertensive therapy, followed mean of 4.6 years (the CHAP study: Cardiovascular Health Awareness Program)
  • Blood pressure measured (as in the SPRINT trial) by AOBP (electronic automated office blood pressure). In Ontario, the protocol was that the person rest seated in a quiet place, undisturbed before and during the readings. The research staff did not speak to the subjects or interact with them. The patient did not wait 5 minutes, but the AOBP recorded the blood pressure each minute for 5 minutes and computed the mean value. The AOBP was recorded in community pharmacies, which a different study found to be similar to AOBP done in the office of the patient’s own family physician. In the SPRINT trial, the initial reading was after the patient seated and wait 5 minutes in quiet, then the blood pressure was measured using a similar automated machine as in the Ontario study
  • Mean age 76, 42% male, 6% self-reported smokers, 48% self-reported high blood cholesterol, 27% diabetic, 12% congestive heart failure
  • Mean AOBP: 134.3/72.9 mmHg. Mean number of antihypertensive meds = 1.8-1.9 for each 10mm blood pressure category

Results:

  • 904 nonfatal and fatal cardiovascular events during the follow-up period
  • Multivariate adjustment (adjusting for age, sex, coronary artery disease, cerebrovascular disease, congestive heart failure, diabetes, number of anti-hypertensive meds, hypercholesterolemia, smoking, self-reported health status, BMI, number of unique drugs) found that, as compared to an achieved systolic of 110-119 mmHg [n=837]:
    • <110 mmHg: HR 1.38 (1.04-1.81) [n=546]
    • 120-129mmHg: HR 1.30 (1.01-1.66)[n=1308]
    • 130-139mmHg: HR 1.23 (0.96-1.58), nonsignificant [n=1259]
    • 140-149mmHg: HR 1.18 (0.90-1.54), nonsignificant [n=984]
    • 150-159mmHg: HR 1.43 (1.08-1.90) [n=604]
    • 160+ mmHg: HR 1.85 (1.42-2.41) [n=645]
  • Multivariate adjustment for achieved diastolic blood pressure, as compared to referent of 60-69 mmHg [n=1788]:
    • <60 mmHg: HR 1.31 (1.07-1.61) [n=636]
    • 70-79 mmHg: HR 1.02 (0.87-1.21), nonsignificant [n=2212]
    • 80-89 mmHg: HR 1.08 (0.88-1.32), nonsignificant [n=1133]
    • 90+ mmHg: HR 1.14 (0.86-1.52), nonsignificant  [n=414]
  • Multivariate adjustment for pulse pressure (systolic minus diastolic), with 50-59 mmHg being referent [no comment on how many people were in each group]:
    • <50 mmHg: HR 1.06 (0.87-1.29), nonsignificant
    • 60-69 mmHg: HR 1.07 (0.87-1.30), nonsignificant
    • 70-79 mmHg: HR 1.10 (0.88-1.38), nonsignificant
    • 80-89 mmHg: HR 1.33 (1.03-1.72)
    • 90+ mmHg: HR 1.83 (1.42-2.34)
  • No difference in outcome in the 1673 patients with diabetes vs the 4510 nondiabetics

Commentary:

  • So, overall, this study found increased CV outcomes in patients with achieved systolic blood pressure below 110 mmHg or if 120-129 mmHg (vs the nadir of 110-119 mmHg), and not again until >150 mmHg; an increase only with diastolics <60 mmHg; and an increase when the pulse pressure was >80 mmHg (the latter likely reflecting stiff arteries, as with diffuse atherosclerosis). By the way, this nadir of SBP 110-119 mmHg was the same as in the SPRINT trial
  • This observational study, as with many observational studies, did find a J-curve in clinical outcomes in hypertensive patients, with increased morbidity/mortality in those with both lower and higher achieved blood pressure. This was not found in the prospective randomized-controlled SPRINT or ACCORD trials, where the lower blood pressure was better, suggesting that there might be a selection bias here: i.e., are those with lower blood pressure different from the others? Do they have non-blood pressure related terminal illnesses, like cancer or infections or perhaps worse cases of diabetes or heart failure, which leads to lower blood pressure and also to higher morbidity/mortality?)
  • One thing I have commented on in the past: there is a rather strong trend in the medical literature to put many study details in a “supplement”, which i think often includes critical details. In the above study, for example, there were no data on the number of patients in each cell of achieved systolic and diastolic blood pressures, except in the supplement, and none anywhere on the pulse pressure categories. It seems to me to be very important information (was the lack of statistical significance in some groups due to small numbers of patients??). My guess is that pretty few readers go to the trouble of going online to get this information; it is much less of a hassle to just accept the authors’ interpretations in the main article. And if we just got the PDF from the author by email, the supplementary material is not included (at least in my experience). And I pretty often do find very important information buried in the supplements, in the relatively few times I scour them, and this information sometimes changes my interpretation of the article.
  • One of my biggest concerns with clinical management of hypertension is that in the typical rushed clinical environment, most of us simply accept the automated blood pressure readings of the medical assistants as being accurate. This brings up several very important issues in probably what is the most common clinical issue we see in adult patients and one that we can potentially positively affect:
  • The automated machine is not always accurate (e.g. in patients with atrial fibrillation or frequent dysrhythmias)
  • Typically the patient walks into the room and has the blood pressure done quickly in a not-so-restful environment (and many of my patients are pretty unfit physically/deconditioned, so have a much much higher blood pressure than when I retake a manual pressure when they are sitting quietly in the exam room)
  • I do routinely recheck blood pressures in the exam room, typically after leaving the patient sitting on the exam table for about 2 minutes, often with the lights out (I go into the other room to write my note), and find in this not-very-scientific study that about 50% of the medical assistant blood pressures are really pretty close to what I get, 40+% are much lower than the medical assistant pressures (and often by 20-40 mmHg!!!), and the rest are much higher than the medical assistant values (not sure why, but i sometimes get manual pressures of 190/108, when the medical assistants get 118/77…..)
  • There is a significant literature suggesting that clinical outcomes track much better with 24-hour ambulatory blood pressure monitoring (ABPM) or home-based blood pressure (I do ask patients to bring in their cuff and make sure it compares well with the manual recording I get, done at the same time). See the URLs below for more articles on this. and the USPSTF does now (finally) endorse non-clinic based blood pressures (see below)
  • Using AOBP in this Ontario study, similar to the SPRINT study, is an interesting hybrid, which sounds pretty good to me, though i have not seen much in the literature on this. But again, to apply these trials to clinical practice, we need to get blood pressure readings that approximate how it was done in the studies (i.e., at least with having the patient rest in a quiet room for awhile, or using ABPM; though with ABPM, there is only one cutpoint: either above or below 135/85, not with the fine gradations of the SPRINT or other trials assessing treating blood pressure to different targets.
  • One of the strengths of this study is that it was not a formal study with selected patients according to specific inclusion and exclusion criteria, but more of a community approach, likely more reflective of our actual clinical practice (i.e., there is decreased internal validity in that there may have been very uneven distribution of patients in the different categories of achieved blood pressure, perhaps with healthier patients overall able to achieve an SBP in the 110-119 range, or their clinicians were more aggressive in trying to lower their blood pressure; yet more external validity in that it more closely reflects real-world clinical practice. one drawback to the study was that AOBP was measured only one point in time. and they did not have much granular data, such as how long the patient had hypertension or what time of day the AOBP was recorded, or how bad the heart failure was, etc. But it was intriguing that the results (best to have SBP 110-119) was so similar to that of the rigorous SPRINT trial.

See http://blogs.bmj.com/ebm/category/hypertension/ for an array of articles/reviews on hypertension, including a recent one showing that blood pressure variability is associated with more cardiovascular disease

See http://blogs.bmj.com/ebm/2015/01/15/primary-care-corner-with-geoffrey-modest-md-uspstf-recs-on-ambulatory-blood-pressure-monitoring/ for a brief review of ambulatory BP monitoring and the USPSTF recommendations

See http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/ for the overall SPRINT trial

See http://blogs.bmj.com/ebm/2016/06/02/primary-care-corner-with-geoffrey-modest-md-sprint-trial-elderly-subgroup-study-of-lower-blood-pressure-goal/ for an analysis of the elderly subgroup of the SPRINT trial, finding improvement in cardiac outcomes in those >75 yo with achieved SBP of 123

See http://blogs.bmj.com/ebm/2016/05/03/primary-care-corner-with-geoffrey-modest-md-home-blood-pressure-monitoring/ for some of the data on home blood pressure monitoring

See http://blogs.bmj.com/ebm/2015/10/13/primary-care-corner-with-geoffrey-modest-md-bp-self-monitoringself-titrating-decreases-bp/ shows the benefits of patient self-monitoring blood pressure and self-titrating meds

Primary Care Corner with Geoffrey Modest MD: Orthostatic Hypotension and Increased Heart Failure and Mortality

19 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There was an interesting subgroup analysis of the ACCORD blood pressure wing (Action to Control Cardiovascular Risk in Diabetes) which found that those with orthostatic hypotension (OH) had a significantly higher risk of mortality and heart failure events (see Fleg JL, Hypertension. 2016;68:888 ). Details:

  • The ACCORD trial had 10,251 high-risk patients with type 2 diabetes, hemoglobin A1c >7.5%, and were between 40 and 79 years old with cardiovascular disease or 55 to 79 years with anatomic evidence of subclinical atherosclerosis, albuminurea, LVH, or >= 2 additional cardiovascular risk factors. 4733 were randomly assigned to intensive vs standard blood pressure control in a non-blinded trial, with target systolic blood pressure (SBP) of <120 vs <140 mm Hg, and with no requirements as to what medications to give (clinicians’ decisions)
  • 4266 participants were involved in this analysis, with blood pressure measured at baseline, and at the 12 month, and 48 month follow-up visits. The blood pressure was measured using an automated oscillometric device after the patient had been seated at least five minutes, with the blood pressure determined three times at one minute intervals. The patients then stood up and had their blood pressure measured every minute for three minutes. The patients were asked if they experienced dizziness or felt light-headed.
  • Orthostatic hypotension (OH) was defined as a decline in SBP > 20 mmHg or decline in DBP > 10 mmHg
  • The average difference in blood pressure achieved between the intensive vs standard groups was 14.2/6.1 mmHg, with the mean number of medications being 3.4 for the intensive group and 2.1 for the standard group.
  • Serious adverse events related to the intervention, including hypotension and syncope, were found in 3.3% of the intensive group compared to 1.3% of the standard group, with p<0.001

Results:

  • OH occurred at least once in 852 people (20.0%). In the adjusted model, this occurred most commonly in women, current smokers, those with higher baseline SBP, higher A1c, and those on beta blockers, alpha blockers or insulin. Of note, neither age nor assignment to intensive vs. standard BP treatment goals was associated with OH
  • Approximate 5% of all patients, independent of group, felt dizzy on standing. The incidence was slightly more in the intensive group but only at the 48 month examination.
  • There was no significant difference in OH prevalence, incidence, or resolution between those in the intensive vs. control groups.
  • People with OH were about twice as likely to report symptoms of dizziness on standing than those without OH, but this was only in about 17-20% of the patients who were symptomatic.
  • Those with OH had an 85% higher risk for heart failure deaths or hospitalizations (p= 0.01) and 62% higher risk for total mortality (p= 0.02).

Commentary:

  • In my experience, beta blockers are the medication most commonly associated with OH and large decreases in blood pressure on standing, even in those with high sitting pressures.
  • It is not so surprising that those with higher A1c’s and on insulin have more OH, since they may well have more autonomic neuropathy, and there may also be some direct insulin-induced vasodilation, perhaps through endothelium-dependent mechanisms.
  • Or that smokers have more OH (probably more atherosclerotic disease of their large arteries, leading to higher SBP but lower DBP because of their nondistensibility)
  • Or in those who had initially higher SBP (again perhaps related to more atherosclerotic large vessel disease, leading to more isolated systolic hypertension)
  • It is, however, unexpected and striking that they found no correlation of OH with age. All of the studies I have seen have shown a significant increase with age. Perhaps part of the reason is that in this study they had an 80-year-old cut off.
  • And, there was no association with whether the patient was in the more aggressive blood pressure lowering group or not (which also supports checking orthostatics in patients with higher blood pressures)
  • So, in this study, it was unclear whether OH was simply a marker of people at higher risk of morbidity/mortality (e.g. more advanced diabetes, with more autonomic neuropathy, etc. as above), or whether it was the cause. but given the not-so-unlikely possibility of the latter being part of the issue, I think it makes sense to assess OH regularly in patients (and i do so in all elderly hypertensive patients, even if they do not have diabetes, and have found, i think, pretty impressive 30+ mmHg drops in blood pressure even in those with systolics in the 150-160 range, and not so uncommonly…) and customize therapy to avoid excessive falls in blood pressure, whether they are symptomatic or not (the reason being: even if asymptomatic, perhaps there are times when they eat/drink less at home or outside in the heat and they become symptomatic, fall, etc; and perhaps the low flow associated with OH really is not so good for the brain, heart, kidneys, etc in the longterm.)
  • For example, there are some studies showing cognitive decline with low blood pressure: see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/).
  • Another important point from the study was that dizziness is not commonly reported with clear-cut OH by blood pressure measurement (i.e. we should not rely on reported dizziness as a reliable marker of OH), and that OH is not a consistent finding each time it is measured.
  • All of this supports my prior suggestions that we measure orthostatic blood pressures in older patients on a regular basis, even if the SBP is in the 150 range, and adjust meds accordingly (?ACCORDingly).

 

(See http://blogs.bmj.com/ebm/2016/05/20/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension-revisited/ for more studies on orthostatic hypotension, including the finding that initial hypotension on standing is in fact much more common than standard orthostatic hypotension after a couple minutes)

Primary Care Corner with Geoffrey Modest MD: Blood Pressure Variability Increases Cardiovasc Disease

4 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There has been concern about the adverse effects of blood pressure variability on cardiovascular outcomes. A prior blog (see http://blogs.bmj.com/ebm/2015/08/10/primary-care-corner-with-geoffrey-modest-md-blood-pressure-variability-and-heart-disease/ ) reviewed the ALLHAT trial, which found that visit-to-visit blood pressure variability was associated with increased CV events and commented on a 2010 issue of the Lancet that found that hour-to-hour BP variability in individuals was associated with more strokes, and, to a lesser degree, coronary events (see Rothwell PM. Lancet 2010;375:895). BMJ just had a systematic review and meta-analysis confirming the association (see doi.org/10.1136/bmj.i4098).

Details:

  • 41 papers representing 19 observational cohort studies and 17 clinical trial cohorts. 24 papers studied long-term variability (monitoring blood pressure in clinics), 4 studies mid-term variability (home monitoring) and 15 short-term (ambulatory blood pressure monitoring).
  • Range of studies: 457 to 122,636 participants; follow-up ranged from 2514 to 490,544 person-years; mean age ranged from 48.5 to 77 yo
  • Increased long term variability in systolic blood pressure was associated with:
    • All-cause mortality: 15% increase, HR 1.15 (1.09 to 1.22)
    • Cardiovascular disease mortality: 18% increase, HR 1.18 (1.09 to 1.28)
    • Cardiovascular disease events: 18% increase, HR 1.18 (1.07 to 1.30)
    • Coronary heart disease: 10% increase, HR 1.10 (1.04 to 1.16)
    • Stroke: 15% increase, HR 1.15 (1.04 to 1.27)
  • Increased mid-term variability (home BP) in daytime systolic blood pressure was associated with all-cause mortality [HR 1.15 (1.06 to 1.26)].
  • Increased short term variability (ambulatory BP) in daytime systolic blood pressure was also associated with all-cause mortality [HR 1.10 (1.04 to 1.16)]. The conclusions are a bit limited, since 2 studies dominated the meta-analysis.

Commentary:

  • As with meta-analyses, they combine different studies with differing methodologies, limiting their conclusions. For example, there is not necessarily any consistency across studies in terms of how the BP was measured, what size cuffs were used, whether using manual or automated devices, etc.)
  • They did not include studies on nocturnal dipping (that’s the normal variation, with lower blood pressure at night on ambulatory monitoring; non-dippers seem to have higher mortality). They did exclude patients on dialysis, since blood pressure variability is basically intrinsic to hemodialysis patients.
  • As a perspective, the 15+% difference in cardiovascular events found still pales in comparison to overall effect of lowering the mean blood pressure. I.e., the primary goal is to decrease the mean blood pressure. That being said, the difference from blood pressure variability in the above meta-analysis did control for the mean blood pressure, revealing an increased risk over the mean BP
  • Blood pressure variability during the day is normal, typically up to the 18/12 mmHg range. This variability is enhanced in those with arterial stiffness (and the above meta-analysis was skewed to older hypertensive patients), which may put these patients at higher CV risk.
  • This all supports the conclusions that:
    • We should be doing more ambulatory or home BP monitoring: several analyses have found that ambulatory or home blood pressure monitoring is superior to office blood pressure at predicting cardiovascular events, perhaps since ambulatory or home measurements are more likely to pick up BP variability.
    • There are likely advantages to using BP meds that produce a more sustained, less variable blood pressure over 24 hours: amlodipine seems to be the best, ACE-I are intermediate (and there are arguments that the increased stroke rate in several studies of ACE-I may be related to the higher blood pressure in the early mornings), and HCTZ up to 25 mg is the worst (for example, see Webb AJS. Lancet 2010; 375: 906). B-blockers are also in the intermediate category.

Primary Care Corner with Geoffrey Modest MD: CPAP Does Not Reduce Cardiovasc Risk

3 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at patients with moderate-to-severe obstructive sleep apnea (OSA) and documented cardiovascular disease (CVD), finding no reduced risk of adverse cardiovascular outcomes by using CPAP (see DOI: 10.1056/NEJMoa1606599).

Details:

  • 2717 patients aged 45-75 who had moderate-to-severe OSA as well as coronary or cerebrovascular disease were randomized to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group)
  • Mean age 61, 81% male, 64% Asian/25% white, 51% with coronary artery disease/49% cerebrovascular disease, 79% hypertensive, 44% stroke, 33% MI, 30% diabetic, 15% smokers, 78% on BP meds/57% statins/75% aspirin/27% diabetic meds, BMI 29, apnea-hypopnea index (AHI) 29 (moderate-to-severe obstructive sleep apnea), 84% snoring almost every day, but minimal daytime sleepiness
  • Primary composite end point was: death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack
  • Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.
  • Results:
    • In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night (in beginning 4.4, decreasing to 3.5 hours/night by 12 months), and the mean AHI decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up, reflecting good control. 42% adhered to treatment for >4 hrs/night.
    • After a mean follow-up of 3.7 years:
      • Primary end-point event occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) [HR 1.10; (0.91 to 1.32) P = 0.34]. No significant effect on any individual or other composite cardiovascular end point was observed, and the trend was actually for more events in the CPAP group.
      • CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood, with greater reductions in anxiety and depression (25-30% lower). no difference in road-traffic accidents or accidents caused by injury
    • No difference in subgroups: region (China vs other), age, sex, severity of OSA, BMI, daytime sleepiness, type of CVD, diabetes.
    • There were differences in patient characteristics in those who used CPAP > vs < 4 hours/night: more were Caucasian/European, men, had baseline CAD, hypertension, and fewer had TIA/stroke. Using propensity-score matching, there were 86 events in the CPAP group and 98 in usual-care: non-significant (i.e., no benefit even in the subgroup who used CPAP for > 4 hours/night)

Commentary:

  • The indications for CPAP seem to continue to decrease over time. There is pretty good documentation that OSA is associated with hypoxemia and sympathetic stimulation, elevated blood pressure especially in the AM, inflammation, oxidative stress, metabolic syndrome/insulin resistance/type 2 diabetes (which seems to independent of the obesity common in both conditions), 2-3x increased risk of NAFLD (also apparently independent of obesity/diabetes), hypercoagulation, right-sided heart failure. There are several observational studies suggesting that there is an association with cardiovascular events (esp stroke). And there are studies finding that using CPAP lowers the blood pressure, but only a little (2-3 mmHg, but can be up to 6-7 mmHg in those with resistant hypertension, though a recent RCT found a 3-4mmHg decrease); and improves insulin sensitivity and endothelial function. And observational studies show that it lowers cardiovascular events in those adherent to treatment. Another study found a 64% relative and 28.5% absolute risk reduction in those using CPAP in a nonrandomized but prospective 6 year study, concluding “OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA” (see Buchner NJ. Am J CritCare Med 2007; 176 (12): 1274), advocating for more aggressive CPAP usage.
  • The concerns about CPAP are: that OSA is remarkably common, including 20-30% of males and 10-15% of females, though this depends on how OSA is defined and what the cutpoints are for the AHI (these percentages are if one uses an AHI>5/hour cutpoint); OSA seems to be much more common in those with underlying cardiovascular disease, cited at 40-60%; but CPAP is a pretty significant intervention (very difficult for many patients to use CPAP machines/uncomfortable, and in this study, the average was only 3.3 hours/night, which is similar to general clinical practice). Using CPAP therefore only makes sense if there is real clinical improvement.
  • A prior study was done in Spain (see Barbe F. JAMA 2012; 307(20): 2161) which randomized 357 patients to CPAP, 366 control. All patients had AHI of  >= 20/hr and no significant daytime symptoms; and they excluded anyone with prior cardiovascular event (i.e., much lower cardiovascular risk than those in the current study). In this 4-year study, as with the above study, there was no difference in cardiovascular events. Of note there was no difference in events when assessing those with the highest AHI levels or % of time with SaO2 <90%. Median CPAP usage was 5 hours, but those who used the CPAP >4 hours did have a 28% [HR 0-.72 (0.52-0.98), p=0.04)] lower incidence of hypertension or cardiovascular event. But looking specifically at cardiovascular events, there was a nonsignificant trend to lower CVD events (I should add here that 60% used the CPAP>4 hours, and this more adherent group may have done other healthy changes to decrease their risk of cardiovascular events. and these healthier things may have influenced the outcome more than the CPAP). Similarly if look at amount of time with SaO2<90%, the less time the fewer events.
  • So, overall, this current study showed very little cardiovascular benefit in many patients at high risk for CVD events and with pretty severe OSA. Although it is true that people used the CPAP only for 3-4 hours/night, this seems to be pretty much the range of usual CPAP usage, and they did find a dramatic decrease in AHI. My sense is that the indications for CPAP, a pretty significant and difficult intervention for many patients, have decreased considerably over time (early commentators suggesting that we should use it to prevent right-heart failure, or improve hypertension control, or decrease cardiovascular events/metabolic syndrome, etc.). Now, by far the major argument for CPAP for the vast majority of people, it seems to me, is for symptom control when patients are not sleeping well and having daytime somnolence or functional/psychological impairment(depression/anxiety, etc.) from inadequate sleep.

Primary Care Corner with Geoffrey Modest MD: ACE Inhibs Decrease Conduction System Disease

11 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A secondary analysis of the ALLHAT hypertension study (see doi:10.1001/jamainternmed.2016.2502 ) found that patients in the lisinopril arm had decreased development of cardiac conduction system disease, which the authors suggested was due to lisinopril’s anti-inflammatory and antifibrotic properties.

Details:

  • ALLHAT was a community-focused hypertension study in 623 North American sites with 3 medication arms: lisinopril, amlodipine, and chlorthalidone. There was also a lipid component, and patients with fasting LDL 120-189 mg/dl (or 100-129 if known atherosclerosis) were randomized to pravastatin vs placebo. Follow-up 5 years
  • 21,004 people: 56% men, mean age 66.5, 92% white/6% black, baseline BP=174/98, BMI 28, Framingham risk score 22%, 16% smokers

Results:

  • 1114 developed conduction system disease: LBBB in 389, RBBB in 570, intraventricular conduction delay in 155
  • lisinopril vs chlorthalidone: 19% reduction in developing conduction system disease [HR 0.81 (0.69-0.95, p=0.01] with lisinopril
  • Amlodipine was non-significantly different from lisinopril

Commentary:

  • It was interesting that in this study no one developed lesser conduction system abnormalities such as 1st degree AV block, LAFB, or incomplete RBBB, which suggests that there might be a different pathophysiology than simply a progression of conduction system dysfunction (e.g. progressive fibrosis of Lev). The data on progression of 1stdegree AV block, for example, are mixed, with some long term studies finding this to be a benign condition, but some studies (e.g. Framingham Study) did find that an increase in atrial fibrillation (HR 2.1), likelihood of progression to require a pacemaker (HR 2.9) and higher all-cause mortality (HR 1.4): see Cheng S. JAMA 2009; 301(24): 2571.
  • LBBB and RBBB are clearly associated with increased cardiac mortality, as well as the potential progression to complete heart block
  • Lisinopril was better than chlorthalidone in this secondary analysis, controlling for an array of clinical variables, including demographics, BMI, smoking, aspirin use, diabetes, CAD, LVH, lipids. And this wasdespite the fact that the achieved blood pressure reduction was inferior with lisinopril.
  • Concerns about the study:
    • This is a secondary analysis, and there was some selection bias (those who received serial EKGs were more likely to be men and white, not have diabetes, and to be on aspirin)
    • >40% of all  participants were on at least one additional step 2 or step 3 drug, which brings up 2 issues:
      • The choice of the second and third agents was prescribed (either atenolol, clonidine or reserpine as step 2, hydralazine as step 3) and these were not standard community practice even at that time, at least in the Boston area (e.g.: adding atenolol to lisinopril was not done much then, since that combo was felt to be less synergistic, both being renin-active agents. The other agents were not used much at all)
      • There were no granular data presented separating out patients just on lisinopril as a single agent vs those on lisinopril in combination. This is problematic if lisinopril plus one of the second line meds did have some synergistic effect in combination for preventing conduction system abnormalities. So, for example, maybe the lisinopril did nothing alone, but did so only in combination with another med. in that case the conclusion that lisinopril is good for protecting the conduction system would be erroneous.
    • If lisinopril were protective, why would that be the case?
      • I think positing the anti-inflammatory effect is a bit of a stretch, since those on pravastatin (a pretty potent anti-inflammatory) had no protection and in fact a trend to worse conduction system disease outcomes
      • Clearly the issue is not lowering the blood pressure per se, since the lisinopril group had less BP improvement
      • My guess is that the issue was decreasing LVH, since LVH was the strongest single predictor of incident conduction system disease in multivariate analysis. (The association with lisinopril above did control for LVH, but only LVH at baseline. And only by the relatively poorly sensitive EKG). And, ACE inhibitors/ARBs are the best agents for reversing LVH. Also, LVH itself does have significant mortality associated with it, which is decreased when an antihypertensive agent decreases EKG-determined LVH (see the LIFE trial, Dahlof B. Lancet 2002; 359: 995, which showed that the ARB losartan was better than atenolol in decreasing cardiac events, but that with LVH regression by either drug, there were fewer cardiac events – i.e., it was the LVH regression that mattered, not the drug. unfortunately, they did not report on conduction system dysfunction). The data on reversal of LVH is almost as good for calcium blockers (e.g. amlodipine) as with ACE inhibitors (e.g. lisinopril). Diuretics (like chlorthalidone) are significantly less likely to reverse LVH.
    • So, my conclusions:
      • This study reinforces my use of dihydropyridine calcium channel blockers as my first drug for hypertensive patients. As mentioned in several prior blogs, I am concerned with using hydrochlorothiazide as the initial agent (the most commonly used one), since its durability over 24 hours is quite limited (see blog below), and this ALLHAT secondary analysis reinforces not using a diuretic. Amlodipine has a much longer duration of action and has much less blood pressure variability (perhaps an additional clinical benefit). This was pretty much the conclusion of NICE, in their 2011 analysis, suggesting that all Afro-Caribbean hypertensive individuals and all white people >55yo have a calcium channel blocker as the first agent. They do suggest an ACE inhibitor if white and <55yo (mostly because of the higher likelihood of high renin hypertension in this  group), though they also supported using chlorthalidone (but not hydrochlorothiazide)
      • And, as in the LIFE study, the current study does support preferentially using an ACE inhibitor or ARB for those with LVH by EKG (and, I would extend this to echo LVH). Though, again, amlodipine (or other dihydropyridine calcium channel blockers) are also reasonable. (i.e., the 2011 NICE guidelines are basically upheld by this study….)

 

See http://blogs.bmj.com/ebm/2016/05/04/primary-care-corner-with-geoffrey-modest-md-chlorthalidone-is-better-than-hctz-for-hypertension/ which showed that HCTZ has poor 24-hr duration, with chlorthalidone being much better

Primary Care Corner with Geoffrey Modest MD: SPRINT Trial: Elderly Subgroup Study of Lower Blood Pressure Goal

2 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A subgroup analysis of the SPRINT trial found improved clinical outcomes in community-dwelling patients >= 75yo on intensive blood pressure control (see doi:10.1001/jama.2016.7050). For an overall review/critique of SPRINT, see http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/.

Details:

  • In brief, the SPRINT trial involved 9361 patients, mean age 68 (but they had a pre-designated subgroup >=75 yo), randomized to SBP goals of <120 vs <140 and achieving SBP of 121 vs 136, then finding a pretty dramatic clinical benefit in those with the more aggressive blood pressure goal. The researchers did not determine the antihypertensives used, but encouraged using those with known cardiovascular benefit (diuretics, calcium blockers, ACE/ARB)
  • The current study is of the 2636 people were over >=75 (mean age 79.9, 38% women, 75% white/17% black/7% Hispanic, baseline BP 142/71, 10% with orthostatic hypotension, creatinine 1.1 mg/dl, eGFR 63, total chol 182/HDL 56, 52% on statin, 10-yr Framingham risk score 25%, mean of 2 antihypertensives, 13% physically fit/55% less fit/32% frail)
  • Results in this older cohort, after 3.14 years (study terminated early):
    • Achieved blood pressure: 123.4/62.0 vs 134.8/67.2; those in the intensive group required average of 1 more antihypertensive (frail patients had SBP difference of 10.8 mm Hg, less fit 11.3 and fit 13.5 mmHg)
    • Primary composite outcome (nonfatal MI, acute coronary syndrome, nonfatal stroke, nonfatal acute decompensated heart failure, death from cardiovascular cause):
      • 102 events in intensive group (2.59%/yr) vs 148 (3.85%/yr) on standard therapy, a 34% reduction [HR 0.66 (0.51-0.85)]. Number-needed-to-treat for 3.14 years was 27
    • Secondary outcome (all-cause mortality):
      • 73 deathsin intensive group vs 107 on standard therapy, a 33% reduction [HR 0.67 (0.49-0.91)].  NNT for 3.14 years was 41
    • Rate of serious adverse events was not statistically different overall, with:
      • Hypotension in 2.4% in intensive vs 1.4% standard, nearly significant trend
      • Orthostatic hypotension at clinic visit in 21.0% vs 21.8%
      • Syncope in 3.0% vs 2.4%
      • Electrolyte abnormalities in 4.0 vs 2.7%, nearly significant trend
      • Acute kidney injury in 5.5 vs 4.0% (leading to hospitalization or were reported in hospital discharge summary), nearly significant trend
      • Injurious falls in 4.9% vs 5.5%
      • And, overall, no increase in the serious adverse events in the frail group

So, several points:

  • The hypertension guideline trend has been for increasingly higher blood pressure goals in the elderly: the European guidelines target initiating treatment only if SBP>160 in those >80 yo; the JNC8 recommendations are for a target of 150 in those >60 yo
  • The SPRINT guidelines did have some really important exclusions: history of diabetes, symptomatic heart failure in past 6 months or LVEF <35%, clinical dementia, prevalent stroke, unintentional weight loss of >10%, an SBP of <110 mmHg after standing for 1 minute, or residing in a nursing home
  • Not surprisingly, the NNT was much lower in this trial than the overall SPRINT trial, given the higher event rate of this older group
  • And, reassuringly re: orthostatic hypotension, this subgroup analysis is pretty convincing that there was no increase, but they did exclude anyone with a standing SBP <110
  • But, a few caveats here:
    • The baseline BP was pretty low: mean 142/71. I would be hesitant to assume the same results would apply to those with baseline BP of 200/100
    • This is a much smaller cohort than the larger study, and the overall SPRINT study did find statistically significant though small increases in adverse effects in the intensive group: for hypotension, syncope, electrolyte disturbances, and acute kidney injury
    • They do not give a breakdown of the age distribution, nor do they do further subgroup analysis to know if the same benefit would apply to those 85 years old or older
    • They did not look at initial orthostatics (see http://blogs.bmj.com/ebm/2016/05/20/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension-revisited/ )which may be more prevalent and important than the usual postural changes that they did assess.
    • I still remain concerned that the diastolic pressures are pretty low (62 range), given that it is in diastole that the coronaries perfuse, and this high risk group likely had some obstructive coronary disease. I do understand that these 3 year results did not show an increase in cardiovascular events/mortality, but I remain a tad skeptical
  • However, this issue of blood pressure goal in older people is really important clinically, since studies such as the Framingham Study have found that about 90% of elderly develop hypertension if they live long enough. Another study found that 75% of those 75 years old have hypertension
  • So, what makes sense for clinical practice?
    • I do think this study, despite above caveats, should inform clinical practice
    • As per my last blog, I do think it is really important to make sure the blood pressure reading we are basing decisions on is really accurate (make sure done correctly, use ambulatory/home monitors,…)
    • I would check orthostatics, including initial orthostatics, on all elderly patients given this lower goal
    • But that being said, I would strongly consider slowly decreasing systolic blood pressure in elderly patients to the low 120 range, with slow incremental med changes, in those with no prior history of diabetes, stroke, or standing BP <110 mm Hg (as excluded in the SPRINT trial).

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