Is there a net benefit to a systolic blood pressure target of 120 mm Hg compared with 140 mm Hg in patients without diabetes who are at high risk of cardiovascular disease?
In this group of older patients (mean age = 68 years) who do not have diabetes but are at high risk of cardiovascular disease, a more aggressive systolic blood pressure target of 120 mm Hg instead of 140 mm Hg led to benefits (lower all-cause mortality, lower cardiovascular mortality, less heart failure), but also some harms (more serious episodes of hypotension, electrolyte abnormality, syncope, and acute kidney injury). Patients in the intensive therapy group took an average of one additional drug to achieve this target. The decision to pursue this more aggressive target should be guided by how well the patient fits the profile of patients in this study (ie, no diabetes, older than 50 years, high risk of cardiovascular disease) and how well the additional therapy is tolerated. (LOE = 1b)(www.essentialevidenceplus.com)
The SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373(22):2103-2116.
Study design: Randomized controlled trial (single-blinded)
Funding source: Government
Setting: Outpatient (any)
Previous trials of more aggressive blood pressure targets in high-risk patients have either shown no benefit, or in some cases a benefit limited to only one of many possible clinical outcomes (eg, hemorrhagic stroke only). This study identified patients 50 years and older with a baseline systolic blood pressure between 130 mm Hg and 180 mm Hg and no history of diabetes mellitus or stroke. All were at increased risk of cardiovascular complications based on at least one of the following: cardiovascular disease, chronic kidney disease (glomerular filtration rate [GFR] = 20 mL/min to 60 mL/min); 10-year cardiovascular risk of 15% or more based on the Framingham risk score, or at least 75 years old. Only outcome assessors were masked to the treatment assignment; patients and their physicians were not. Details regarding allocation concealment were not provided, but the groups were balanced with regard to demographics, baseline blood pressure, and cardiovascular risk factors. Of 14,692 patients screened for eligibility, 9361 were randomized to either a systolic blood pressure target of 120 mm Hg or 140 mm Hg. The mean age of participants was 68 years, 56% were current or former smokers, 30% were non-Hispanic black, and 11% were Hispanic. The most common reasons for exclusion prior to randomization were lack of cardiovascular risk, out-of-range systolic blood pressure, or were the use of too many blood pressure medications. The protocol for the 120 mm Hg group specified beginning with 2- or 3-drug therapy with a combination of a thiazide diuretic, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and/or a calcium channel blocker; those in the 140 mm Hg group were converted from their usual drug to an equivalent in the formulary. The formulary included a broad range of medications, including most of the drugs most commonly prescribed in the United States. The exception was that hydrochlorothiazide was only available in combination with triamterene at a dose of 50 mg; chlorthalidone, furosemide, spironolactone, and amiloride were the other diuretics. Drugs were added from the formulary as needed to achieve blood pressure targets. The average number of agents used in the 120 mm Hg group was 2.7, with 32% of patients requiring 3 drugs and 24% of patients requiring 4 or more drugs. In the 140 mm Hg group, the average number of medications was 1.8, only 17% of patients required 3 drugs, and 7% required 4 or more. Clinical outcomes and adverse events were adjudicated by a committee masked to treatment assignment. Analysis was by intention to treat, and the mean blood pressures achieved in the 2 groups were 121 mm Hg and 136 mm Hg. Although the study originally planned a 5-year follow-up, it was halted after 3.3 years on the basis of positive findings in an interim analysis. The intensive treatment group was less likely to die from any cause (3.3% vs 4.5%; P = .003; number needed to treat [NNT] = 83 over 3.3 years), less likely to die from a cardiovascular cause (0.8% vs 1.4%; P = .005; NNT = 167 over 3.3 years), and less likely to develop heart failure (1.3% vs 2.1%; P = .002; NNT = 125 over 3.3 years). There were no significant differences in the likelihood of myocardial infarction, acute coronary syndrome, or stroke. Among the patients with chronic kidney disease at baseline (n = 2646), there was no difference in the likelihood of end-stage renal disease or a 50% or higher reduction in GFR. Among those without chronic kidney disease, there was a small increase in the likelihood of a 30% or greater decline in GFR (3.8% vs 1.1%; P = .001; NNT = 37 over 3.3 years). The benefits became apparent after 2 to 3 years of therapy based on the Kaplan-Meier curves. Looking at a composite outcome of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death, benefits appeared to be somewhat greater among patients older than 75 years and for men. Although there were clear benefits, there were also harms. Serious adverse events were defined as fatal or life-threatening, resulting in disability, or requiring hospitalization. Episodes of hypotension (2.4% vs 1.4%), syncope (2.3% vs 1.7%), electrolyte abnormality (3.1% vs 2.3%), and acute kidney injury or acute renal failure (4.1% vs 2.5%) were all significantly more common in the intensive therapy group.
Mark H. Ebell, MD, MS
University of Georgia
In patients with an intermediate risk for cardiovascular disease, does blood pressure lowering (regardless of initial blood pressure) improve clinical outcomes?
This large trial provides important guidance for primary care physicians and their patients. For patients at intermediate risk of cardiovascular (CV) disease who have a systolic blood pressure lower than 143 mm Hg, there is no benefit to prescribing candesartan plus hydrochlorothiazide. For those with elevated blood pressure, there is a small benefit in terms of the composite outcome (number needed to treat [NNT] = 59 over 5.6 years to prevent one CV death, nonfatal MI, or nonfatal stroke) but no mortality benefit. The recent SPRINT trial found a benefit, but in a much higher risk group. This study supports current recommendations for limiting use of antihypertensives in low-risk and intermediate-risk patients to those with a systolic blood pressure higher than 140 mm Hg. (LOE = 1b)(www.essentialevidenceplus.com)
Lonn EM, Bosch J, Lopez-Jaramillo P, et al, for the HOPE-3 Investigators. Blood-pressure lowering in intermediate risk persons without cardiovascular disease. N Engl J Med 2016;374(21):2009-2020.
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry + govt
This is part of a large Canadian-led international trial that simultaneously evaluted the effect of blood pressure lowering and cholesterol lowering in patients at intermediate risk for CV disease, but who had no known CV disease at trial entry. The trial was co-sponsored by Astra-Zeneca, but their role was limited to providing the trial drug and having one member on a 24-person steering committee. The researchers enrolled men older than 55 years and women older than 65 years with at least one risk factor, and women older than 60 years with 2 risk factors; approximately half the patients were Asian. Patients with and without hypertension were included. On average the patients were at intermediate risk, defined as a 10-year risk of a CV event of approximately 10%. A total of 14,682 patients entered a run-in phase to assess for compliance and adverse drug effects, and 12,705 completed the run-in and were randomized to receive either candesartan 16 mg plus hydrochlorothiazide 12.5 mg or placebo. The groups were balanced at the start of the study, analysis was by intention to treat, and the study was powered to detect a 22% relative reduction in the "coprimary outcomes." (I know, I know, "primary" means 1 outcome, not 2.) The average age of participants was 66 years, 46% were women, and 22% were already taking an antihypertensive medication other than one of the study drugs. Patients were followed up for a median of 5.6 years. The mean blood pressure at the start of the trial was 138/82 mm Hg, and the active treatment group had their blood pressure lowered by 6 mm Hg more than the placebo group (10.0 vs 4.0 mm Hg). As noted above, the authors looked at coprimary composite outcomes: (1) CV death, nonfatal myocardial infarction, and nonfatal stroke; and (2) those outcomes plus resuscitated cardiac arrest, heart failure, and need for revascularization. At the end of the trial, there was no significant difference between groups in these 2 outcomes (4.1% vs 4.4% and 4.9% vs 5.2%, respectively), as well as no difference in the rates of death from CV causes (2.4% vs 2.7%) and all-cause mortality (5.4% vs 5.5%). The researchers had prespecified an analysis stratified by the initial blood pressure. For patients with an initial blood pressure higher than 143.5 mm Hg (the upper tertile) there was a significant reduction in the likelihood of both coprimary outcomes: For the composite of nonfatal myocardial infarction, nonfatal stroke, and CV death, it was 4.8% vs 6.5% (hazard ratio = 0.73, 95% CI 0.56 - 0.94; NNT = 59 over 5.6 years to prevent one event).
Does intensive lowering of blood pressure improve the lives of patients with hypertension?
Patients with hypertension who are treated intensively are less likely to have major cardiovascular events, stroke, or progression of albuminuria or retinopathy than those treated less intensively, but intensive lowering had no meaningful effect on myocardial infarctions, heart failure, or mortality. (LOE = 1a)(www.essentialevidenceplus.com)
Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 2016;387(10017):435-443.
Study design: Meta-analysis (randomized controlled trials)
This team of researchers searched several databases and registries to identify randomized trials that lasted at least 6 months and that compared more intensive versus less intensive blood pressure lowering in patients with hypertension. Two authors independently determined which studies to include and assessed the included studies' methodologic quality. They were interested in a range of clinically meaningful outcomes (eg, mortality) as well as irrelevant outcomes (eg, progression of albuminuria), singly or as a composite. Ultimately they included 21 reports from 19 trials with nearly 45,000 patients followed up for an average of 4 years. Approximately half the studies were of modest to poor quality. The intensive treatment group had mean blood pressure levels of 133/76 compared with 140/81 in the less-intensive group. The data show small reductions in the rate of major cardiovascular events (5.7% vs 5.8%; number needed to treat [NNT] = 838) and stroke (2.4% vs 2.6%; NNT = 406), but no significant reduction in the rate of myocardial infarctions (2%). Although there were decreases in the rates of albuminuria progression and retinopathy progression, there were no significant decreases in the rates of heart failure, end-stage kidney disease, overall mortality, or cardiovascular mortality. Most studies failed to report on the harms of intensive blood pressure lowering. In the 6 studies that did, serious harms occurred in 1.2% per year in the intensive group versus 0.9% per year in the nonintensive group, with severe hypotension occurring 0.3% per year versus 0.1%. Finally, patients with pre-existing diabetes, renal disease, or vascular disease treated more intensively generally had better outcomes than those treated less intensively.
Henry C. Barry, MD, MS
Michigan State University
East Lansing, MI
In persons at intermediate risk for a cardiovascular event, does medication to reduce blood pressure and cholesterol reduce the likelihood of cardiovascular events?
This large and well-executed trial confirms that treating elevated blood pressure reduces the likelihood of cardiovascular (CV) events and that statins provide a consistent relative reduction in risk, regardless of the baseline risk. But the absolute risk reduction is lower and the number needed to treat (NNT) is higher when the person starts at a lower baseline risk. Statins at a dose similar to that given in this study reduce the likelihood of a CV event by approximately 25%. So, if you are starting at a 10-year risk of 20%, that gets you down to 15%, for an NNT of 20. Pretty good. If your 10-year risk is 10%, as in this population, it reduces your likelihood to 7.5%, for an NNT of 40. If your 10-year risk is only 5%, it takes you down to 3.75%, for an NNT of 80. These numbers should be the basis of our discussions with patients about statins. (LOE = 1b)(www.essentialevidenceplus.com)
Yusuf S, Lonn E, Pais P, et al, for the HOPE-3 Investigators. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016;374(21):2032-2043.
This is part of a large clinical trial that evaluted the simultaneous effect of blood pressure lowering and cholesterol lowering in patients at intermediate risk for CV disease. The researchers enrolled men older than 55 years and women older than 65 years with at least one CV risk factor, and women older than 60 years with 2 risk factors. The patients had an average 10-year risk of having a CV event of 10%, which the authors categorized as intermediate risk. Astra-Zeneca provided the medications and had one member on a 24-person steering committee. After a run-in period to identify compliant patients without adverse events (something that creates a bias in favor of the drug) patients were randomized into 1 of 4 groups: candesartan- hydrochlorothiazide (HCTZ) plus rosuvastatin, candesartan-HCTZ plus placebo, rosuvastatin plus placebo, or placebo plus placebo. Two other articles compared the effects of candesartan-HCTZ versus placebo and rosuvastatin versus placebo; this one only compares the patients who received both drugs (n = 3180) with those who received only placebos (n = 3168). The previous trials found small benefits to rosuvastatin (NNT = 91 to prevent one CV event over 5.6 years) and a similar benefit to giving the blood pressure medicines to patients with a systolic blood pressure higher than 143 mm Hg (but not to those with normal blood pressure). As with the other 2 reports, patients in this trial had a mean age of 67 years, 46% were women, groups were balanced at the start of the study, and analysis was by intention to treat. The primary outcome was a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke: Patients who received candesartan-HCTZ plus rosuvastatin had a somewhat lower likelihood of this outcome, but the likelihood was similar to that in the rosuvastatin study (3.6% vs 5.0%; P = .005; NNT = 67 over 5.6 years). As with the individual drug comparison studies, there was no change in CV deaths or all-cause mortality. Prespecified subgroup analyses by sex, age, race, or ethnicity did not reveal any heterogeneity of benefit.
In patients with resistant hypertension (poor control despite the maximum dosages of 3 drugs), what is the most effective add-on medication?
In the short term, spironolactone is most effective at lowering blood pressure in patients with resistant hypertension. Whether this will result in better long-term control or decrease the rate of clinically important outcomes—such as stroke, congestive heart failure, kidney failure, and so forth—is unknown. (LOE = 2b)(www.essentialevidenceplus.com)
Williams B, MacDonald TM, Morant S, et al, for the British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015;386(10008):2059-2068.
Study design: Cross-over trial (randomized)
Many guidelines recommend the A+C+D approach to managing patients with hypertension: start with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, add a calcium channel blocker, then a diuretic.* Once patients are taking maximum dosages of all 3 drugs, then what? These authors enrolled 335 such patients in a randomized cross-over trial to see which of the following was more effective in lowering blood pressure: spironolactone, doxazosin, or bisoprolol. To be eligible, the patients had to be aged between 18 and 79 years, have systolic blood pressure (SBP) 140 mm Hg or greater in the office plus home SBP 130 mm Hg or greater in spite of maximum dosages of all 3 drugs. This was a 12-month study that began with all patients receiving a placebo during the first month followed by 6 weeks of low dosages of either spironolactone (25 mg daily), doxazosin (4 mg daily), or bisoprolol (5 mg daily) followed by 6 weeks of double doses (if tolerated). In most cross-over studies, there is a washout period between each treatment interval to minimize the potential for carryover effect of the previous treatment. These authors did not include washout intervals but tried to account for this by doing a sensitivity analysis comparing individual active treatment periods with the initial placebo period. The primary outcome was the average of 18 home SBP readings ascertained on 4 consecutive days. Unfortunately, 21 patients never "played at all" and only 234 patients completed all of the treatment cycles. However, the researchers reported having at least 274 patients for any single treatment period. Compared with the other drugs, the average reductions in SBP for spironolactone, doxazosin, and bisoprolol were 9 mm Hg, 4 mm Hg, and 4 mm Hg, respectively (P < .001). Compared with placebo, the reductions were 13 mm Hg, 9 mm Hg, and 8 mm Hg, respectively. The rate of serious adverse events was comparable in each group (2%-3%) as was the rate of all adverse events (15%-23%). *The Eighth Joint National Committee gives equal weight to each of 3 strategies: (1) push drugs to maximum dosage before adding an additional drug, (2) add a second agent before pushing initial agent to maximum dosage, and (3) start with 2 medications then titrate to maximum dosage. It also gives no preference to initial medication choice among "A, C, or D."
How urgently should we aim to control hypertensive urgency?
It seems that rapid treatment of patients with hypertensive urgency is both unsuccessful and unnecessary. In this study of almost 60,000 patients, 80% did not have controlled blood pressure (< 140/< 90 mm Hg) after 1 month of treatment, including patients who were hospitalized. On the other hand, the risk of a major cardiovascular event was also low: 1 in 1000 over the next 7 days. (LOE = 2b)(www.essentialevidenceplus.com)
Patel KK, Young L, Howell EH, et al. Characteristics and outcomes of patients presenting with hypertensive urgency in the office setting. JAMA Intern Med 2016;176(7):981-988.
Study design: Cohort (retrospective)
Funding source: Self-funded or unfunded
These authors identified all patients in a single healthcare system (N = 58,535) who presented to an office or emergency department with a blood pressure of at least 180 mm Hg systolic and/or 110 mm Hg diastolic. Most of the patients in the analysis just met these minimums; only 10.2% had a systolic pressure of 200 mm Hg or higher and 5.7% had a diastolic pressure of 120 mm Hg or higher. The mean age of the patients was 63.1 years, 57.7% were women, and 76% were white. A small proportion (0.7%) were hospitalized for blood pressure management; however, half of these patients had pressures of at least 200 mm Hg systolic or at least 120 mm Hg diastolic. Regardless of treatment or place of treatment, both the likelihood of blood pressure control and the likelihood of adverse effects were low. At 1 month, less than 15% of patients had controlled blood pressure; at 6 months, less than 40% had controlled blood pressure. Even so, the likelihood of a major adverse cardiovascular event was low in the next 7 days (0.1%), at 8 to 30 days (0.2%), or within 6 months (0.9%). Hospitalization was not associated with a decrease in the risk of adverse outcomes.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
POEMs are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, please see http://www.essentialevidenceplus.com(www.essentialevidenceplus.com).
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