The Shep Trial (1991)
JNC published it’s first set of guidelines in 1977. In 1984, it published JNC 3. In this version, it noted systolic and diastolic blood pressure in it’s diagnosis of hypertension, but treatment goals focused on the achievement of particular diastolic pressures. JNC 3 targeted a DBP <90mmHg in patients, but mentioned isolated systolic HTN (defined as SBP at least 160mmHg and DBP <90) special category and that there was no good evidence for reduction of cardiovascular risk to lower systolic pressures specifically (Carey 1984). In elderly patients with isolated systolic HTN, JNC 3 recommended first recommending sodium reduction and weight loss. If treatment was decided upon, it recommended first treating to a SBP of 140-160mmHg and, if this was tolerated, treating to a SBP <140mmHg. This was somewhat of a gray area and fell more into the category of individualization and taking the whole patient into consideration rather than clear-cut guidelines.
This is where the SHEP Trial came into play. For the SHEP Trial, it was unknown whether treatment of isolated systolic hypertension resulted in reduction of cardiovascular events. This trial enrolled 551 patients at least 60yo with isolated systolic hypertension. The primary outcomes were fatal and nonfatal stroke. Patients were randomized to chlorthalidone or placebo. The outcome of the trial was that chlorthalidone is effective for lowering BP in elderly patients with systolic HTN and decreases stroke and CV mortality.
SHEP TRIAL: SHEP Cooperative Research Group. (1991). Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). Jama, 265(24), 3255-3264.
SHEP Trial PMID: 2046107
Useful summaries of the SHEP Trial: cardiologytrials.org
Other References:
Carey, R. M., Cutler, J., Friedewald, W., Gant, N., Hulley, S., Iacono, J., ... & Weiss, S. (1984). The 1984 Report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. Archives of Internal Medicine, 144(5), 1045-1057.
The Syst-Eur Trial (1997)
The story for this trial actually started with a pilot trial that was published in 1991 (Amery 1991). In this pilot trial publication, it was noted that the European Working Party on High Pressure in the Elderly (EWPHE) trial which looked at patients with a minimum age of 60 years and a blood pressure of 160-239/90-199 showed that antihypertensive treatment led to a decrease in cardiovascular mortality. It was also noted that 1988, several trials for antihypertensive drug treatment had been published, but most studies included only young and middle-aged patients. Some trials at this time had recruited older patients, but there was still no strong evidence that antihypertensive treatment in the elderly improved total mortality. It noted that until 1988, all published trials mainly recruited patients mainly on the basis of diastolic blood pressure elevation, but that in industrialized countries and diastolic blood pressure peaks at an age of 50 and then stabilizes or decreases. The investigators for this trial decided to test the hypothesis that drug treatment of isolated systolic hypertension would lead to a reduction in cardiovascular mortality and morbidity.
As noted, during the onset of this trial, there were still some uncertainties about the benefit for treatment of isolated systolic hypertension in the elderly. There was also some controversy about calcium channel blockers as first-line agents and evidence was lacking that these agents reduced cardiovascular risk. The trial went on to enroll patients at least 60 years old with isolated systolic HTN. The trial enrolled 4695 patients in 198 medical centers across 23 countries in Western and Eastern Europe. The patients were randomly assigned to active treatment or placebo. Active treatment included a dihydropyridine calcium channel blocker called nitrendipine with the possible addition of enalapril and hydrochlorothiazide. The trial was stopped early because the trial had reached a primary endpoint of a significant benefit for stroke. At a median of two years of follow-up, it was found that active treatment led to a reduction in the total rate of stroke from 13.7% to 7.9%. Non-fatal stroke, all fatal and nonfatal cardiac in points including sudden death, were decreased significantly in the active treatment group. The information that this study gives us is that among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with a dihydropyridine calcium channel blocker reduces the rate of cardiovascular complications.
Syst-Eur Trial: Staessen, J. A., Fagard, R., Thijs, L., Celis, H., Arabidze, G. G., Birkenhäger, W. H., ... & Forette, F. (1997). Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Lancet, 350(9080), 757-764.
Syst-Eur Trial PMID: 9297994
Useful summaries of the Syst-Eur Trial: cardiologytrials.org
Other References
Amery, A., Birkenhäger, W., Bulpitt, C. J., Clement, D., De Leeuw, P., Dollery, C. T., ... & O’Brien, E. T. (1991). Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization. Aging Clinical and Experimental Research, 3(3), 287-302.
The DASH Trial (1997)
When the research for the DASH Trial was undertaken by the researchers, it was noted that 24% have United States adults had hypertension. Is also noted that the current-guidelines recommended weight control, reduced intake of sodium, reduce alcohol consumption, and possibly an increase dietary potassium intake as lifestyle modifications. It was known that vegetarian diets reduce blood pressure possibly due to intake of more potassium, magnesium, fiber, calcium or through reduced fat intake. Trials had studied the changes in blood pressure when intake of these above items, was changed individually, but blood pressure reduction was inconsistent. The discrepancy between the blood pressure effects of the vegetarian diet and the trials of individual nutrient modification set the stage for the DASH Trial. It was speculated that there was a limited benefit of single nutrient supplementation and that a more holistic vegetarian diet could reduce blood pressure due to the combination of a wide variety of nutrient changes. This trial set out to study the benefit of making this combination of changes.
This trial enrolled 459 adults at least 22 years of age who were not taking antihypertensives with SBP < 160mmHg and DBP of 80-85mmHg. The length of the trial was 11 weeks including a three week run-in period and an eight week intervention period. All participants were given a controlled diet as part of a run-in period which is similar to that of the typical Western diet for a length of three weeks. At that point, the participants were divided into three groups and given different diets for a length of three weeks. One group was given a typical Western diet (called the control diet). A second group was given a diet rich in fruits and vegetables. A third group was given a combination diet (later termed the DASH diet). This combination diet was a combination of a diet that was rich in fruits and vegetables as well as low-fat dairy products with reduced saturated and total fat. Importantly, the sodium intake of all 3 groups was this same at 3 grams of sodium intake per day. They attempted to keep weight the same during the trial, but weight changes were -0.1kg, -0.3kg, and -0.4kg in the control, fruits-and-vegetables, and combination diets, respectively.
The fruits-and-vegetables provided a potassium and magnesium consumption close to the 75th percentile of U.S. consumption. The combination diet did the same. A 7 day menu with 21 meals at for caloric levels (1600, 2100, 2600, and 3100 Calories) was developed for each diet. The food was prepared and research kitchens according to a common protocol. Each week day, the subjects ate lunch or dinner on-site. After that meal, they were given coolers that contained the to be eaten off-site. On Fridays, they were given weekend meals to be consumed at home. The subjects were told to not drink more than 3 caffeinated beverages per day, no more than 2 alcoholic beverages per day. There also given 2 packets of salt each containing 2000mg of sodium that could be used at their discretion. Their weight was monitored each weekday and was kept stable by adding 100 Calorie cookies or muffins as needed. The outcome measured in this study was blood pressure.
At baseline, the mean blood pressure was 131.3/84.7mmHg. Among all participants, the combination diet reduced blood pressure by 5.5/3.0mmHg as compared to the control diet. The fruits-and-vegetables diet reduced blood pressure by 2.8/1.1mmHg as compared to the control diet.
This study included 133 patients with hypertension defined as a SBP > 140mmHg and DBP >90, or both. Among the hypertensive patients, the combination diet reduced blood pressure by 11.4/5.5mmHg as compared to the controlled diet. The conclusion of the trial was at a diet rich in fruits, vegetables, and low-fat dairy foods with reduced saturated and total fat can substantially lower blood pressure, even similar to that of antihypertensive drug monotherapy.
One of the interesting things about this study was the fact that low-fat dairy products reduced blood pressure greater than the fruits-and-vegetables diet. In the book Hypertension: A Companion to Braunwald’s Heart Disease, it noted that there has been some speculation about the reason for the additional benefit the combination diet as compared to the fruits and vegetables diet. Apparently, compared with fruits and vegetables diet, the combination diet had more vegetables, more low-fat dairy products, and more fish, and was lower and red meat, sugar, and refined carbohydrates. I have not found a better explanation for this other than one was noted in this book.
Overall, this is a great study with applications to how we should be counseling our hypertension patients. Of course consideration would need to occur in those with more advanced CKD to avoid hyperkalemia or other metabolic abnormalities.
DASH Trial: Appel, L. J., Moore, T. J., Obarzanek, E., Vollmer, W. M., Svetkey, L. P., Sacks, F. M., ... & Lin, P. H. (1997). A clinical trial of the effects of dietary patterns on blood pressure. New England journal of medicine, 336(16), 1117-1124.
DASH Trial PMID: 9099655
Useful summaries of the DASH Trial: Wiki Journal Club
The HOT Trial (1998)
At the time this trial was published, it was known that patients with treated hypertension had a higher incidence of cardiovascular complications as compared to normotensive individuals. It was suspected that inadequate reduction of their blood pressure was the most likely cause, but the optimum target blood pressure was not known at this time. It was estimated that less than 30% of patients with hypertension have blood pressures better lowered less than140/90,supporting a hypothesis that inadequate reduction of blood pressure on treatment led to this increased cardiovascular risk. Conversely, there were concerns that aggressive blood pressure lowering could lower the blood pressure to the point of increased cardiovascular complications in line with the J-curve concept. This trial set out to determine the correct blood pressure target.
In addition, aspirin had been shown to reduce the incidence of stroke and MI given long-term to healthy individuals of those with existing cardiovascular disease, but its use in those without established cardiovascular disease was unknown. This trial also aimed to determine its efficacy for this purpose.
This trial randomized 18,790 patients from 26 countries that were aged 50 to 80 years old with hypertension and DBP 100-115mmHg. They randomized the patients to a target diastolic blood pressure of either less than 90mmHg, less than 85mmHg, or less than 80mmHg as well as to aspirin or placebo. Felodipine was used as the first-line agent. If additional therapy was needed, ACE or BB were added with subsequent maximization of dosage and finally, the addition of a diuretic if needed to achieve BP targets. DBP was reduced by 20.3mmHg, 22.3mmHg, and 24.3mmHg among the three target groups… a tight grouping of achieved blood pressures which made interpretation of the results difficult.
The trial gave us a few pieces of information. Before we go any further, it’s important to note that there was no placebo group. All patients were treated, but the only difference was the degree to which blood pressure was lowered (although it was a tight grouping of BPs between the three groups). Firstly, there was no difference in cardiovascular mortality or overall mortality between the three groups, meaning that there was no benefit to aggressive BP lowering from this standpoint. Cardiovascular risk was lowered in the group targeted to a DBP <80mmHg as compared to the target of <90mmHg only in those with diabetes. Aspirin was found to reduce CV events and MI, but had no effect on stroke.
A strange thing about this trial is that the authors seemed to draw the wrong conclusion about the study. During my reading on the trial, I got confused as to what the actual conclusion of the trial should be. The above statements are my best attempt at this. There was some controversy about the fact that the authors noted reductions in CV events even though there were no statistically-significant findings in the trial to support this. There were also comments made after the publication of the trial noting that pulse pressure among participants should have been investigated more closely and included in the final analysis. The links below to Lancet letters to the editor are good commentaries on this trial
The HOT Trial: Hansson, L., Zanchetti, A., Carruthers, S. G., Dahlöf, B., Elmfeldt, D., Julius, S., ... & HOT Study Group. (1998). Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. The Lancet, 351(9118), 1755-1762.
HOT Trial PMID: 9635947
Useful summaries of the HOT Trial:
Lancet letter to the editor #1
Lancet letter to the editor #2:
The LIFE Study (2002)
The main question is if among hypertensive patients with left ventricular hypertrophy, does losartan prevent more cardiovascular morbidity and death compared to atenolol? When this trial was being designed, it was well-known that blood pressure treatment results in benefit to patients. It was noted, however, that if hypertensive patients were treated, increased cardiovascular morbidity and mortality remained. It was suspected that this increased risk to patients may result from a failure to achieve normal blood pressure, residual target organ damage (such as left ventricular hypertrophy), or both.
The trial was designed based on several assumptions and observations. It was known that beta-blockers and diuretics do not return CV morbidity and mortality to levels seen in patients without hypertension. It was known that left ventricular hypertrophy (LVH) was an independent risk factor for CV complications in hypertension and it was known that angiotensin II (ang II) was associated with development of LVH. Experimental evidence had shown that blocking ang II resulted in benefits beyond blood pressure lowering alone.
This trial studied losartan (the first available ARB) versus atenolol (considered first-line treatment for hypertension at the time). The trial randomized 9,193 patients aged 55-80 years old with previously treated or untreated hypertension and ECG signs of LVH. Exclusion criteria included patients with secondary hypertension; myocardial infarction or stroke within the previous 6 months; angina pectoris requiring treatment with β-blockers or calcium-antagonists; heart failure or left ventricular ejection fraction of 40% or less; or a disorder that, in the treating physician's opinion, required treatment with losartan or another angiotensin-II type 1-receptor antagonist, atenolol or another b-blocker, hydrochlorothiazide, or angiotensin- converting-enzyme inhibitors.The trial randomized patients to Llosartan- or atenolol-based antihypertensive therapy. The primary outcome was a composite endpoint comprised of CV death, myocardial infarction, and stroke.
Follow up occurred for at least 4 years until 1040 patients experienced the primary outcome. Blood pressure fell to a similar degree between the two groups, but the losartan-based group had a 13% relative risk reduction as compared to the atenolol-based group. The conclusion of the trial was that losartan provided cardiovascular benefit beyond simply blood pressure lowering.
The LIFE Study: Dahlöf, B., Devereux, R. B., Kjeldsen, S. E., Julius, S., Beevers, G., de Faire, U., ... & Lindholm, L. H. (2002). Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. The Lancet, 359(9311), 995-1003.
LIFE Study PMID: 11937178
Useful Summaries of the LIFE Study: Wiki Journal Club
The AASK Trial (2002)
This trial randomized 1,094 African American adults with hypertension and CKD (defined by a GFR 20-65 mL/min/1.73 m2) without a clear secondary cause of CKD to a BP target [intensive BP with MAP ≤92 mm Hg (equivalent BP of 130/80) or usual MAP 102-107 mm Hg (equivalent BP of 140/90)] and BP agent (ramipril, amlodipine, or metoprolol) in a 2x3 factorial design. The primary outcomes were the slope of eGFR change and progression of CKD or death. The secondary outcome was a composite outcome that included a reduction in eGFR by 50% or by 25mL/min/1.73m2, ESRD, or death. After the original AASK trial, a 5 year (2002-2007) cohort study of AASK participants took place (Appel 2008)
At 4 years, there was no difference in the primary outcome by BP target in the population as a whole. Also, there was no specific medication associated with a reduction in eGFR slope. Rampirl, though, reduced the secondary composite outcome as compared to amlodipine and metoprolol. As mentioned above, in all study participants, a more aggressive BP reduction was not associated with better renal outcomes. However, when participants with UPCR > 0.22 (median proteinuria in these patients was 1000mg/day) were examined, there was a reduction in primary outcome in the trial phase. A reduction in the primary outcome and the secondary outcomes were reduced when both trial and cohort phases were taken into account (Appel 2010).
Use of the ACE-inhibitor ramipril was associated with fewer CKD events (slowing the rate of GFR decline) or death. The AASK trial in part solidified the use of ACE-inhibitors among patients with CKD. In summary, this trial gave us 3 pieces of information, that more intensive BP management in CKD did not result in an improvement in renal outcomes in this population as a whole, but ACE inhibitors did. It also showed that in patients with significant proteinuria (~1g/day), intensive BP control resulted in improvement in renal outcomes.
The AASK Trial: Wright Jr, J. T., Bakris, G., Greene, T., Agodoa, L. Y., Appel, L. J., Charleston, J., ... & Hebert, L. (2002). Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. Jama, 288(19), 2421-2431.
AASK Cohort Study: Appel, L. J., Wright, J. T., Greene, T., Kusek, J. W., Lewis, J. B., Wang, X., ... & Contreras, G. (2008). Long-term effects of renin-angiotensin system–blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in african americans. Archives of Internal Medicine, 168(8), 832-839.
AASK Trial PMID: 12435255
Useful summaries of the AASK Trial: Wiki Journal Club
Other references: AASK Trial investigator publication that synthesizes the results of the original AASK Trial and the Cohort phase: Appel, L. J., Wright Jr, J. T., Greene, T., Agodoa, L. Y., Astor, B. C., Bakris, G. L., ... & Gabbai, F. B. (2010). Intensive blood-pressure control in hypertensive chronic kidney disease. New England Journal of Medicine, 363(10), 918-929.
The ALLHAT Trial (2002)
The main question was that if in patients with hypertension, what is the efficacy of a calcium channel blocker, ACE inhibitor, or thiazide diuretic in lowering the incidence of CV events? This trial randomized 33, 357 patients to either get chlorthalidone, amlodipine, or lisinopril for blood pressure control. There were an additional 9061 patients they were randomized to doxazosin but this arm was stopped early due to evidence of increased harm. The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction. The main outcome was that there is no significant difference between the primary outcome for Lisinopril, chlorthalidone, or amlodipine. The main question for this study was a pretty timely one. At the time of the study, calcium channel blockers and ACE inhibitors were newer and more expensive than chlorthalidone. Pfizer had patent protection on amlodipine until 2007. Patent protection for Lisinopril lasted until June of 2002. What this study contributes overall to medical knowledge was that the more expensive medications of amlodipine and lisinopril at that time were no better than the more cost-effective chlorthalidone.
The ALLHAT Trial: Furberg, C. D., Wright, J. T., Davis, B. R., Cutler, J. A., Alderman, M., Black, H., ... & Oparil, S. (2002). Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Journal of the American Medical Association, 288(23), 2981-2997.
ALLHAT PMID: 12479763
Useful summaries of the ALLHAT Trial: Wiki Journal Club
The ACCOMPLISH Trial (2008)
Before this trial, no single antihypertensive was proven to be significantly better than others. The ALLHAT Trial, which was published in 2002, did not clearly demonstrate a difference between a single agent diuretic, an ACE inhibitor, or a calcium channel blocker (CCB). At the time, JNC 7 recommended combination blood pressure regimens for those with BP >20/10 above target and that diuretics should be considered. Experimental evidence prior to this trial, though, showed that CCBs increased vascular endothelial nitric oxide and that the addition of an ACE inhibitor increases nitric oxide levels more than either drug alone. This combination was shown in laboratory animals to slow the progression of atherosclerotic lesions and in humans, this combination reduced LVH and arterial stiffness. Because of these findings, it was proposed that combinations that do not include diuretics be considered.
The ACCOMPLISH Trial enrolled 11,506 patients and randomized them to getting either benazepril and amlodipine or benazepril and hydrochlorothiazide. The inclusion criteria were patients at least 55 years with HTN and high CV risk. The primary outcome was the time to first CV event (defined as the composite of a cardiovascular event and death from cardiovascular causes). The trial was terminated early after a mean follow-up of 36 months.
The primary outcome events were lower in the benazepril + amlodipine group than the benazepril-HCTZ group, 9.6% versus 11.8 (~20% reduction in primary outcome). One criticism of the trial was the use of the short-acting diuretic hydrochlorothiazide rather than the longer-acting chlorthalidone. It's said that this may have contributed to the worse event rate with benazepril + hydrochlorothiazide group. Evidence to support this concern was the fact that the MRFIT trial which was published in 1990 changed its protocol to include chlorthalidone rather than hydrochlorothiazide because of a nonsignificant trend towards worst outcomes of hydrochlorothiazide. Despite these concerns, a 2010 follow-up study from the ACCOMPLISH trial offers measured blood pressure continuously in 573 patients and there is no difference in 24 hour blood pressures for either group — indicating that the findings of the trial were more sound than detractors would make it out to be (Jamerson 2011).
The ACCOMPLISH Trial: Jamerson, K., Weber, M. A., Bakris, G. L., Dahlöf, B., Pitt, B., Shi, V., ... & Velazquez, E. J. (2008). Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. New England Journal of Medicine, 359(23), 2417-2428.
ACCOMPLISH Trial PMID: 19052124
Useful Summaries of the ACCOMPLISH Trial: Wiki Journal Club
Other References:
Jamerson, K. A., Devereux, R., Bakris, G. L., Dahlöf, B., Pitt, B., Velazquez, E. J., ... & Weber, M. A. (2011). Efficacy and duration of benazepril plus amlodipine or hydrochlorthiazide on 24-hour ambulatory systolic blood pressure control. Hypertension, 57(2), 174-179.
The HYVET Trial (2008)
When this trial was being designed, there was accumulating evidence that treatment of blood pressure across a broad range of patients was beneficial for reducing cardiovascular events. it was not known however, if the same treatment benefits apply to those over 80 years old. Most HTN trials by this time had excluded patients over 80 years old and a noted inverse correlation of blood pressure and risk of death among elderly was known at the time. Although this inverse correlation may have been due to confounders associated with low BP (i.e. cancer, dementia, MI, heart failure), there were real concerns about treating patients with hypertension in this age range. A retrospective cohort analysis was mentioned in the introduction of the HYVET Trial (Oates 2007) which showed shorter survival for >80 year old patients who were treated with antihypertensive medications and had a SBP <140mmHg. Overall, it was suspected that there was benefit to treating hypertension in these patients, but the benefits were unknown and a fear of increased harm was very present.
This trial enrolled 4,761 very elderly individuals (at least 80 years old) he had persistent HTN (defined as SBP 160-199). after a two-month run in Phase, 3845 patients were randomized to active treatment with blood pressure medications or a placebo. patients in the act of treatment arm utilizing a thiazide diuretic (indapamide) and possibly an ACE (perindopril) and other antihypertensive medications, if needed, to target a goal BP of <150/80mmHg. The primary end point was the rate of fatal or nonfatal stroke (excluding TIA). Secondary end points included death from any cause, death from cardiovascular causes, death from cardiac causes, and death from stroke. The median follow-up was 2 years. Although there was no statistically-significant difference in the primary end point between the two groups (P=0.06), there was a 21% reduction in the rate of death from any cause (P=0.02). There was also a 64% reduction in the rate of heart failure (P=<0.001). The trial results did note the non-significant outcomes of a 30% reduction in the rate of fatal or non-fatal stroke, a 39% reduction in the rate of death from any stroke, a 23% reduction in the rate of death from CV causes. You may be wondering what the blood pressure reduction in the control group was, being that they used a placebo. In the placebo group, the BP was reduced by about 15/7mmHg. As expected, the active treatment group BP was reduced more — by about 30/13mmHg. Overall, the trial did show that there was benefit to treatment of HTN in patients 80 years old or older in regards to death from any cause with trends toward a reduction in stroke.
The HYVET Trial: Beckett, N. S., Peters, R., Fletcher, A. E., Staessen, J. A., Liu, L., Dumitrascu, D., ... & Belhani, A. (2008). Treatment of hypertension in patients 80 years of age or older. New England Journal of Medicine, 358(18), 1887-1898.
HYVET Trial PMID: 18378519
Useful Summaries of the HYVET Trial: Wiki Journal Club
Other Useful References:
Oates, D. J., Berlowitz, D. R., Glickman, M. E., Silliman, R. A., & Borzecki, A. M. (2007). Blood pressure and survival in the oldest old. Journal of the American Geriatrics Society, 55(3), 383-388.
The SPRINT Trial (2015)
Prior to the publication of the SPRINT Trial, the main evidence only showed benefit to lowering systolic BP <150mHg (SHEP and Sys-Eur Trials) and less data showing benefit to lowering BP slightly lower than that. At the time, JNC recommended lowering BP to <140/90. Well-known evidence noted that cardiovascular risk rose starting at a BP of 115mmHg remained (Collaboration 2002), but prospective trial data on BP interventions to back this observation continually slipped between the fingers of investigators. The burning question that we all had was why there was no evidence for benefit to lower BP targets. The ACCORD BP Trial, published in 2010, showed no benefit for the primary outcome to lowering BP to a goal of <120mmHg as compared to <140mmHg. There was a signal for the benefit of intensive BP control benefit as there there was a reduction in the secondary outcome of stroke with intensive BP control. Additionally, when standard glycemic control combined with intensive BP control in the ACCORD BP Trial was was assessed, there was a reduction of CV outcomes by 26% as compared to standard glycemic and standard BP interventions.
The question remained -- was there a benefit to lowering SBP more than just a goal of <140/90. In the words of the SPRINT Trial investigators ”The hypothesis that a lower systolic blood pressure goal (e.g., <120mmHg) would reduce clinical events more than a standard goal was designated by a National Heart, Lung, and Blood pressure Institute (NHLBI) expert panel in 2007 as the most important hypothesis to test regarding the prevention of hypertension-related complications among patients without diabetes.” The stakes were large. The 2011-2014 NHANES survey estimated a 29% prevalence in HTN so it was possible that millions of individuals were subjected to increased CV related morbidity and mortality due to a lack of evidence for lower BP targets. What was needed was a well-executed trial that could give better guidance to this for HTN management. Years and years had passed without a good answer to this looming question. Had the trial name “COURAGE” not already been used by the interventional cardiologists, it could have been a reasonable alternative name for the SPRINT Trial. The SPRINT investigators were charged with making a well-designed trial that would either show positive findings or show well-founded negative findings (without the usual trial limitations of insufficient sample size, insufficient follow up, lower than expected event rate, blah, blah, blah, ect.). A poorly executed trial could have set the field back for years. The investigators nailed this trial though and it provided evidence that has been improving the outcomes for hypertensive patients since.
The SPRINT Trial, funded by the NIH, enrolled 9361 patients at least 50 years old with a SBP of 130-180mmHg and an increased risk of CV events defined by one or more of the following:
clinical or subclinical CV disease other than stroke
CKD with an eGFR 20-60,
a 10yr risk of CV disease of 15% or greater based on the Framingham risk score
an age of 75 years or older.
The main exclusion criteria were an eGFR <20, proteinuria estimated at >1g per day, polycystic kidney disease, diabetes mellitus, prior stroke, a SBP >180mHg, heart failure (or LVEF <35%), or adherence concerns. 14,692 were screened and 9361 underwent randomization. Out of the people that were not randomized, 2284 were taking too many medications or had SBP out of range. 718 were not at increased CV risk, 587 did not give consent, 653 did not complete screening, 352 had low systolic BP at 1 min standing, 703 had miscellaneous reasons, and 34 were too young.
Participants were assigned to a SBP <140mmHg or <120mmHg. Why did they use SBP targets rather than DBP? It’s because SBP is more strongly associated with CV risk than DBP. This concept is most concisely stated in section 2.2 of the 2017 AHA HTN guidelines (Whelton 2017). Patients with diabetes were not included. Medications encouraged in the trial were chlorthalidone, dihydropyridine CCB, ACE or ARB as initial medications with BB for those with CAD and loop diuretics for those with advanced CKD recommended. BP was measured in clinic by non-observed AOBPM with an average of 3 blood pressure readings taken in the same sitting. It is commonly said that patients were alone for rest prior to BP readings and for all BP readings, but this was not the case. Around 40% were along for the entirety of the rest period and BP measurement, around 20% were alone for the rest period, but not for BP measurement, and 25% were never alone. Importantly, the measured BP was similar among these groups (Johnson 2018). The primary outcome was a composite outcome of MI, ACS not resulting in MI, stroke, acute decompensated heart failure, or death from CV causes. Secondary outcomes included the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.
One important aspect of this trial was the excellent separation in blood pressures between the two groups. This separation occurred by one year into the trial and was maintained (achieved BPs of 121.4 in the intensive treatment group vs 136.2 in the standard-treatment group). Remember that separation of BPs in the HOT Trial (1998) made it difficult to interpret trial results. Achieved BPs are very important in these trials.
The trial was stopped early after a median follow-up of 3.26 years due to a significantly-lower rate of the primary outcome, heart failure, and death in the intensive BP group. Since the primary outcomes was a composite outcome, it’s important to look at the benefit of BP control to the individual components of the primary outcome. The composite primary outcome was mainly driven by a reduction in heart failure and death. Intensive BP had no effect on MI, ACS, or stroke. These were secondary outcomes though and I’m honestly not sure if the trial was powered to detect a difference for individual secondary outcomes. I plan on running a twitter pole for this to get input from the stats geniuses on the findings of these secondary outcomes. These benefits were even seen in patients 75 years old and older. One additional outcome was a decrease of eGFR of at least 50% in patients with baseline CKD. There was no difference between BP target groups for this outcome. The number of renal events was lower than expected and the trial was terminated early which may have contributed to this finding.
Hypotension, syncope, electrolyte abnormality, and AKI were more common in the intensive BP group. Following up on the AKI finding, an AJKD article showed that urinary biomarkers of tubular damage were not elevated in those with a fall in eGFR (Malhotra 2019). This means that the lower eGFRs in the intensive BP group were due to a hemodynamically-mediated fall in GFR without actual kidney damage.
So now to the big question: why did the SPRINT Trial show benefit to intensive BP control and the ACCORD Trial did not? Firstly, the SPRINT Trial had twice the number of participants. Secondly, the ACCORD Trial used a factorial design that funneled patients with hyperlipidemia to the cholesterol intervention rather than the ACCORD BP trial. This may have negatively affected trial enrichment in the ACCORD Trial. The combination of these things may have led to the discrepancy of trial results between SPRINT and ACCORD BP. It is important to note that in the ACCORD BP subset of patients randomized to standard glycemic control and intensive BP control major CV outcomes were reduced. This dovetails with SPRINT findings. When implementing SPRINT findings in everyday practice, it’s important to note BP measurement techniqures. The BP measurement in SPRINT technique results in lower SBP than routine office BP measurement -- largely around 5-10mmHg lower, but as much as ~13mmHg lower (Agarwal 2017, Drawz 2018).
All in all, the SPRINT Trial was a momentous achievement for nephrology and public health considering the staggering number of individuals with hypertension. The NNT to treat for the primary outcome is only 61. This is fantastic. You could conceivably prevent the primary outcome in 3-4 days of clinic. Hypertension is important, fixable, and we can make a big difference for our patients.
The SPRINT Trial: SPRINT Research Group. (2015). A randomized trial of intensive versus standard blood-pressure control. New England Journal of Medicine, 373(22), 2103-2116.
The SPRINT Trial PMID: 26551272
Useful summaries of the SPRINT Trial:
Other References:
Agarwal, R. (2017). Implications of blood pressure measurement technique for implementation of Systolic Blood Pressure Intervention Trial (SPRINT). Journal of the American Heart Association, 6(2), e004536.
Collaboration, P. S. (2002). Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet, 360(9349), 1903-1913.
Johnson, K. C., Whelton, P. K., Cushman, W. C., Cutler, J. A., Evans, G. W., Snyder, J. K., ... & Lewis, C. E. (2018). Blood pressure measurement in SPRINT (systolic blood pressure intervention trial). Hypertension, 71(5), 848-857.
Malhotra, R., Craven, T., Ambrosius, W. T., Killeen, A. A., Haley, W. E., Cheung, A. K., ... & Ix, J. H. (2019). Effects of intensive blood pressure lowering on kidney tubule injury in CKD: a longitudinal subgroup analysis in SPRINT. American Journal of Kidney Diseases, 73(1), 21-30.
Staessen, J. A., Fagard, R., Thijs, L., Celis, H., Arabidze, G. G., Birkenhäger, W. H., ... & Forette, F. (1997). Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Lancet, 350(9080), 757-764.
Whelton, P. K., Carey, R. M., Aronow, W. S., Casey, D. E., Collins, K. J., Himmelfarb, C. D., ... & MacLaughlin, E. J. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 71(19), e127-e248.