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Evidence-Based Argument Against Benefit on Cardiovascular Risk Reduction

  1. Top of page
  2. Evidence-Based Argument Against Benefit on Cardiovascular Risk Reduction
  3. Lower BP Goal and Nephropathy Progression
  4. References

Most guidelines uniformly recommend a blood pressure (BP) goal of <130/80 mm Hg for patients with diabetes or chronic kidney disease (CKD).1,2 These recommendations originated from retrospective data analyses that demonstrate an association between a lower BP with slower decline in CKD and greater cardiovascular (CV) risk reduction among patients with diabetes. The question debated, therefore, is whether evidence from appropriately powered prospective outcome trials truly shows that lower BP further reduces CV risk and CKD progression.

Meta-analyses of prospective clinical trials, to date, demonstrate that reducing BP decreases risk for stroke and coronary heart disease. No trial, however, has achieved a mean office BP reading of <130/80 mm Hg based on a randomization scheme tied to outcomes.3 In trials such as the United Kingdom Prospective Diabetes Study (UKPDS),4 the conventional systolic BP was >10 mm Hg higher than the lower goal, but that was still above 130/80 mm Hg. Nevertheless, there was no difference in CV outcomes between groups based on BP differences.

One prospective study that achieved BP goal around 130/80 mm Hg in patients with diabetes and no overt nephropathy was the Appropriate Blood Pressure Control in Diabetes (ABCD) trial.5 While the trial demonstrated reduced risk for CV events overall, there was no difference between the groups with a mean systolic pressure of 138 mm Hg vs the intensive group at 132 mm Hg.

A review of all trials in patients with diabetes, including the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, makes it clear that while BP reduction to levels below 140/90 mm Hg are associated with fewer CV events, no data support a reduction to levels below 130/80 mm Hg.6

ACCORD provides the definitive answer regarding whether lower levels of BP reduce CV risk compared with conventional BP control.7 This prospective randomized trial clearly demonstrates a separation of mean systolic BP of 14 mm Hg (133 mm Hg vs 119 mm Hg). In spite of this sustained difference in BP for more than 4 years, there was no additional benefit on the primary end point, ie, CV events. There was a benefit, however, on stroke events, albeit, at a cost of a higher side effect profile from medications.

Additional findings from post hoc analyses of the Ongoing Telmisartan Alone and In Combination With Ramipril Global Endpoint Trial (ONTARGET) and International Verapamil SR–Trandolapril Study (INVEST) also corroborate the findings of ACCORD. Post hoc analyses of these trials demonstrate that the benefit of lower levels of BP on CV risk reduction is lost when systolic BP levels fall below 130 mm Hg.8,9 INVEST further demonstrated an increase in CV events at systolic BPs <115 mm Hg, although 100% of these patients had coronary artery disease.9

These studies taken together indicate that in patients older than 50 years with long-standing hypertension and coronary disease, either, overt or covert, reduction of systolic BP below 130 mm Hg does not further reduce CV risk. Moreover, as was noted in ONTARGET and INVEST a systolic BP <130 mm Hg will increase CV risk. The exception, however, is stroke reduction, which has shown a linear benefit between level of BP and risk reduction.

Lower BP Goal and Nephropathy Progression

  1. Top of page
  2. Evidence-Based Argument Against Benefit on Cardiovascular Risk Reduction
  3. Lower BP Goal and Nephropathy Progression
  4. References

More than a dozen appropriately powered prospective outcome trials examined the role of various antihypertensive agents on CKD progression. Only two trials, however, examined whether a lower BP level slowed nephropathy progression. The Modification of Diet in Renal Disease (MDRD) trial was the first randomized trial to examine whether 15-mm Hg lower mean arterial pressure would result in a slower decline in CKD and reduce the risk for renal replacement therapy.10 This trial largely recruited patients with advanced nondiabetic kidney disease, mean baseline glomerular filtration rate (GFR) of 39 mL/min, and >500 mg/d of proteinuria. It failed to show a benefit of the lower BP goal on slowing progression after a 3-year follow-up. After a 12-year follow-up, however, patients with >1 g/d of proteinuria randomized to the low BP group, ie, mean BP of 92 mm Hg, manifested a significant decrease in proteinuria and rate of CKD progression.11 Of note was that the mean systolic BP in the low target group was 126.2±13.6 mm Hg during this follow-up period. Also noteworthy was that a slowed CKD progression was obvious 1 year after the formal trial ended.

The second trial to examine prospectively the effects of different BP levels on nephropathy progression was the African American Study of Kidney Disease (AASK).12 It examined more than 1000 African American patients with a glomerular filtration rate (GFR) assessed by iothalamate, between 20 mL/min/1.73 m2 and 65 mL/min/1.73 m2, and albuminuria. It failed to show a benefit of a lower BP level, ie, 140/82 mm Hg vs 128/77 mm Hg, on CKD progression. It did show a trend toward a slower decline in CKD progression among the subset of patients (5%) with ≥1 g/d of proteinuria. Unlike the MDRD, however, an additional 5-year follow-up, yielding a 10-year total follow-up after randomization, produced no additional benefit on slowing of CKD progression in the lower BP group.13 These data provide support that a BP goal <130/80 mm Hg will yield a greater benefit in slowing CKD in a subgroup of patients with advanced proteinuric nephropathy, but not for the CKD group as a whole.

The totality of the data from appropriately powered randomized trials, therefore, supports a strong association between a systolic BP of <140 mm Hg in reducing CV risk and CKD progression in patients with diabetes. The data supporting a BP <130/80 mm Hg for overall CV and CKD event reduction, however, are very weak and hold only for stroke risk reduction among patients with diabetes and slowed CKD progression in patients with a GFR <45 mL/min/1.73 m2 who have >500 mg of proteinuria.

References

  1. Top of page
  2. Evidence-Based Argument Against Benefit on Cardiovascular Risk Reduction
  3. Lower BP Goal and Nephropathy Progression
  4. References
  • 1
    Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:12061252.
  • 2
    Mancia G, De BG, Dominiczak A et al. 2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:11051187.
  • 3
    Staessen JA, Li Y, Thijs L, et al. Blood pressure reduction and cardiovascular prevention: an update including the 2003–2004 secondary prevention trials. Hypertens Res. 2005;28:385407.
  • 4
    Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:17551762.
  • 5
    Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(suppl 2):B54B64.
  • 6
    Kalaitzidis R, Bakris GL. Lower blood pressure goals for cardiovascular and renal risk reduction: are they defensible? J Clin Hypertens (Greenwich). 2009;11:345347.
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    Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:15751585.
  • 8
    Sleight P, Redon J, Verdecchia P, et al. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens. 2009;27:13601369.
  • 9
    Cooper-Dehoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304:6168.
  • 10
    Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754762.
  • 11
    Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med. 2005;142:342351.
  • 12
    Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:24212431.
  • 13
    Appel LJ, Wright JT Jr, Greene T, et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363:918929.