Primary Care Corner with Geoffrey Modest MD: Blood Pressure Variability and Heart Disease

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By: Dr. Geoffrey Modest

The Annals of Intl Medicine recently published an article on the relationship between visit-to-visit variability of blood pressure and coronary heart disease (CHD), stroke, heart failure and mortality (see doi:10.7326/M14-2803). This was a post hoc analysis of the large database from the ALLHAT study (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).  ALLHAT was an NIH and NHLBI funded study, and one of the best studies from a primary care perspective in that it really was community-based, with 623 clinical sites in the US, and included a truly ethnically diverse population (45% non-Hispanic white, 30% non-Hispanic black, 15% Hispanic white and 3% Hispanic black) to look at the effects of antihypertensives (one of its wings) in adults >55 yo with at least one CHD risk factor. Details:stestoskop-64276_640

  • 25814 patients with at least 7 visits during the study, noting the visit-to-visit variability (VVV) of blood pressure on clinical outcomes. Blood pressure was assessed in a structured and consistent way (though there were lots of sites and there might have been some differences).
  • Those without a clinical CVD (cardiovascular disease) event during the first 28 months were then followed until the end of the study, for mean of 2.7-2.9 more years with max of 5.7 years.
  • Results:
      • Total clinical events: 1194 fatal CHD or nonfatal MI, 1948 deaths, 606 strokes, 921 heart failure events
      • Higher SBP standard deviation (SD) was found in older (67.4 vs 65.7 yo) and non-Hispanic black persons (39.9 vs 25.5%), less likely to be men (47.1% vs 55.3%), less likely to take aspirin (32.1 vs 36.2), less likely to have an HDL<35 mg/dL (9.1 vs 14.3%), did have a higher mean SBP (144.2 vs 132.7 mmHg) and higher pulse pressure (64.0 vs 54.4 mmHg).
      • Those in the highest quintile also were more likely to have low medication adherence (18.1 vs 10.3%), be on more antihypertensive meds (2.0 vs 1.4), have more changes in medication classes (64.1 vs 27.3%) and be more likely to be randomized to lisinopril (30.0 vs 20.9%), and less likely to get chlorthalidone (41.2 vs 49.6%) or amlodipine (22.8 vs 29.5%)
      • After multivariate adjustment, including controlling for mean systolic blood pressure (SBP), Hazard Ratio comparing those with the highest vs lowest quintile of standard deviation of SBP (which was >=14.4 mmHg vs <6.5 mmHg):
        • Fatal CHD or nonfatal MI: HR 1.30 (1.06-1.59)
        • All-cause mortality: HR 1.58 (1.32-1.90)
        • Stroke: HR 1.46 (1.06-2.01)
        • Heart failure: HR 1.25 (0.97-1.61)
      • Higher VVV in diastolic blood pressure was also associated with CVD events and mortality
      • On review of their figures of cumulative incidence of events, overall they are splaying apart as time goes on (ie, more of an effect)

Comments:

      • A pretty quick and dirty secondary analysis of a complex study, finding major differences between the quintiles of VVV. Although their subgroup analysis did find the highest hazard ratio for low medication adherence (HR around 2, and statistically significant, for both fatal CHD/nonfatal MI and for all-cause mortality), they still found a higher CVD and mortality risk after adjusting for this.
      • There is a reasonable putative mechanism for the VVV/CVD relationship: there is a higher VVV of blood pressure when there is more arterial stiffness (lower aortic distensibility), endothelial dysfunction, and (probably) subclinical inflammation.
      • There was a whole issue (pretty unusual) of the Lancet in 2010 devoted to blood pressure variability and CVD (4 articles, for example see Lancet 2010; 375: 895–905), finding that high VVV was associated with an adjusted HR for stroke in the UK-TIA aspirin trial of 4.84 (comparing highest vs lowest decile), 4.29 for the ASCOT-BPLA atenolol group and 4.39 amlodipine group, 1.78 in the European Stroke Prevention Study, and 3.35 in the Dutch TIA study (see their table 2). These are all post-hoc analyses, as is the current study, but they do provide pretty strong support.
      • There are several studies (including ALLHAT) finding an increased incidence of stroke in patients on ACE inhibitors.
      • Studies of 24-hour efficacy of antihypertensives have found that amlodipine and diuretics have the least variation during 24 hours, and b-blockers and ACE-inhibitors have much more (eg, see  Lancet 2010; 375: 867–869​). That being said, there are data suggesting that HCTZ 12.5 mg is not so great, but that chlorthalidone or HCTZ at higher dose, such as 50mg, does decrease 24 hour variability. and, it might be significant that the quintile with highest VVV in the current study were disproportionately on lisinopril. (One argument around strokes is that Lisinopril has waning effects in the wee hours of the morning, and stroke is more common at that time). The potential connection between 24-hr blood pressure variability and SBP variation in different visits is that patients may take their pills at different times, and the med with the least consistent 24-hour effect is more likely to have more VVV, and this may also be especially true when their blood pressure checked at different visits scheduled at different times of the day.
      • So, VVV in blood pressure probably predicts a less good outcome. We might use that as surrogate marker of higher risk and treat risk factors even more aggressively (eg lipids, smoking, etc, and reinforcing lifestyle issues).
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