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The STOP-2 Trial (1999)
This trial was design to address the uncertainty around the cardiovascular benefits of newer antihypertensive medications (ACE inhibitors and CCBs) with older medications (diuretics and beta blockers). This trial enrolled 6614 patients 70-84 years old with BP at least 180/105mmHg. Patients were randomly assigned to conventional drugs (atenolol, metoprolol, pindolol, or HCTZ plus amiloride) or to newer drugs (enalapril, lisinopril, felodipine, or isradipine). The primary endpoint was a combined endpoint of fatal stroke fatal MI, and other fatal CV disease. There was no difference in the primary outcome of the new drugs and older drugs. Limitations to this trial include the fact that it was open-label. This could have influenced the assessment of some cardiovascular events which rely on the presence of signs and symptoms. In addition, there was considerable cross-over in the trial -- only 61-66% of patients were still on their originally-intended randomized medications at the end of the trial.
The STOP-2 Trial: Lindholm, L. H., Hansson, L., Dahlouf, B., Ekbom, T., Hedner, T., De Faire, U., ... & Wester, P. O. (1996). The Swedish Trial in old patients with hypertension-2 (STOP-hypertension-2): a progress report. Blood pressure, 5(5), 300-304.
The STOP-2 Trial PMID: 8879603
Useful Summaries:
The VALUE Trial (2003)
This was a large trial which aimed to determine if treatment with valsartan would be superior to amlodipine-based treatment for the primary composite endpoint of cardiac morbidity and mortality. This trial enrolled paitents at least 50 years old with hypertension. It was a multicenter, double-blind, randomized, prospective clinical trial which enrolled 12,570 patietns. Patients were either randomized to amlodipine-based antihypertenensive therapy or to valsartan-based antihypertnesive therapy. HCTZ and other medications were added as needed to achieve a target of <140/90mmHg. Patients were followed for 30 months. Interestingly, the trial authors seemed to jettison the primary outcome intent of the trial and only report on how well BP was controlled and how their algorithm for HTN management was benefiticial in the office setting. This is strange. The academic community must have thought the same as The VALUE Trial has only been cited in thirteen PubMed Central papers. Despite the name, the VALUE Trial added little value to the academic literature. The primary outcome was not different between the two groups. BP control was achieved in both groups, but BP was slightly lower in the amlodipine-based group.
The VALUE Trial: Julius, S., Kjeldsen, S. E., Brunner, H., Hansson, L., Platt, F., Ekman, S., ... & Weber, M. (2003). VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk. American journal of hypertension, 16(7), 544-548.
The VALUE Trial PMID: 12850387
The CHARM Trial (2003)
This trial was three trials in one, but the overall goal of the trial was to see if the addition of candesartan reduced mortality and hospitalizations a broad spectrum of symptomatic heart failure. As mentioned the trial was split into three parallel trials and grouped by ejection fraction and if they were or were not tolerant of an ACE inhibitor. CHARM Added addressed those with a LVEF of 40% or less who were already on an ACE, and yes, an ARB was added to their ACE inhibitor. CHARM Alternative also addressed those with a LVEF of 40% or less, but who were not tolerant of an ACE, using candesartan instead. Lastly, CHARM Preserved addressed those with a LVEF of >40% who were not already on an ACE. The primary endpoint of the overall CHARM Trial, which pooled results of all three individual CHARM Trials was all-cause mortality. The primary outcome of the individual CHARM Trials was the combined endpoint of cardiovascular mortality or heart failure hospitalization.
The three trials were double-blind randomized placebo-controlled trials which, when combined, included 7601 patients who were assigned candesartan or placebo. Median follow up was 37.5 months. The primary outcome -- all-cause mortality was not significantly different between the two groups. Secondary outcomes were 1) the combined endpoint of CV mortality, nonfatal MI, and hospitalization for heart failure; 2) combined all-cause hospitalization and all-cause mortality; 3) combined hospitalization, all-cause mortality, CV mortality, nonfatal MI, and hospitalization for the management of heart failure; 4) resource utilization, safety, and tolerability; and 5) new diabetes. Candesartan was associated with a reduction in cardiovascular mortality as well as CHF hospitalizations. Among the three individual trials, there was a reduction in CV mortality and hospitalization for CHF in the CHARM Added and CHARM Alternative trials, but not the CHARM Preserved Trial.
The overall CHARM Trial: Pfeffer, M. A., Swedberg, K., Granger, C. B., Held, P., McMurray, J. J., Michelson, E. L., ... & CHARM Investigators and Committees. (2003). Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. The Lancet, 362(9386), 759-766.
The overall CHARM Trial PMID: 13678868
The CHARM Added Trial: McMurray, J. J., Östergren, J., Swedberg, K., Granger, C. B., Held, P., Michelson, E. L., ... & CHARM Investigators and Committees. (2003). Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. The Lancet, 362(9386), 767-771.
The CHARM Added PMID: 13678869
The CHARM Alternative Trial: Granger, C. B., McMurray, J. J., Yusuf, S., Held, P., Michelson, E. L., Olofsson, B., ... & CHARM Investigators and Committees. (2003). Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. The Lancet, 362(9386), 772-776.
The CHARM Alternative PMID: 13678870
The CHARM Preserved Trial: Yusuf, S., Pfeffer, M. A., Swedberg, K., Granger, C. B., Held, P., McMurray, J. J., ... & CHARM Investigators and Committees. (2003). Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet, 362(9386), 777-781.
The CHARM Preserved PMID: 13678871
Useful Summaries:
The STENO-2 Trial (1999)
Diabetes is a difficult disease to treat. The disease can progress with seemingly appropriate medication prescription as management of this disease requires changing an entire lifestyle. For a patient to thrive, it requires management of diabetes, blood pressure, hyperlipidemia, and addressing the associated increased cardiovascular risk. The STENO-2 Trial was one of the main trials that addressed multifactorial risk factor reduction for patients wtih diabetes. This trial enrolled 160 diabetic patients between the ages of 40-65 years old with microalbuminuria (defined as urine albumin excretion rates of 30-300 mg/day -- in line with CKD stage A2 albuminuria). Patients were randomized to conventional therapy or an intensive therapy regimen which included lifestyle modification (low fat diet, light/moderate exercise 3-5 days per week, smoking cessation, vitamin C, vitamin E), blood glucose control to a Hb A1c of <6.5%, BP goal of <140/90 for the initial part of the trial and then <130/80 for the latter part of the trial. They also placed patients on an ACE regardless of BP, lipid-lowering therapy, and aspirin. Both the conventional therapy arm and intensive therapy arm received individualized diabetic dietary advice. The primary endpoint was a composite endpoint of cardiovascular death, non-fatal MI, CABG, stroke, amputation, or peripheral vascular surgery). After a mean follow-up of 7.8 years, patients in the intensive therapy arm had a risk reduction of 57%. The intensive therapy arm also had lower rates of progression to nephropathy, progression of retinopathy, and progression of autonomic therapy. Being a multifactorial risk reduction study, this study addressed the marked benefit of controlling diabetes from every angle. Using multiple interventions, it could not determine which intervention had the most benefit, but this particular question was not the main aim of the trial. Overall, this was a nice study that shows the benefit of what we try to accomplish for diabetic patients in our clinic.
The STENO-2 Trial: Gæde, P., Vedel, P., Parving, H. H., & Pedersen, O. (1999). Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. The Lancet, 353(9153), 617-622.
The STENO-2 Trial PMID: 10030326
The RENAAL Trial (2001)
At the time of this trial, it was known that ACE inhibitors or ARBs delay the progression of renal disease in patients with type 1 diabetes and non diabetic patients who have a overt property. However, it was unknown if this benefit extended to patients with type 2 diabetes. This trial was designed to examine just that. This trial enrolled 1513 patients aged 31 to 70 years old who had type 2 diabetes and nephropathy. Nephropathy was defined as a presence of ACR of at least 300mg/g or a rate of protein excretion of at least 500mg/day in patients with a serum creatinine of 1.3-3.0mg/dL. During a six-week screening phase, patients received their standard in hypertensive therapy. If they were on ACE or ARBs, they were transitioned to alternative medications. They were then randomized to losartan or placebo with other BP medications as needed to target a BP of <140/90. The primary outcome was the time to the first event of the composite end point of a doubling of serum creatinine, ESKD, or death. ESKD was defined as the need for long-term dialysis, or death. The mean follow-up time was 3.4 years. Losartan led to a 16% risk reduction for the primary outcome. This was a well-designed trial that added to our knowledge of the benefits of ACE and ARBs.
The RENAAL Trial: Brenner, B. M., Cooper, M. E., De Zeeuw, D., Keane, W. F., Mitch, W. E., Parving, H. H., ... & Shahinfar, S. (2001). Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New England journal of medicine, 345(12), 861-869.
The RENAAL Trial PMID: 11565518
Useful Summaries:
The IDNT Trial (2001)
At the beginning of this trial, it was unknown whether or not ARBs reduce the progression of diabetic nephropathy independently of its capacity to lower blood pressure. This trial randomized 1715 hypertensive patients with chronic kidney disease attributed to type 2 diabetes. Patients where are eligible if they were between the ages of 30 and 70 years old, had hypertension with a blood pressure of greater than 135/85mmHg, had type 2 DM, and had a urinary protein excretion of at least 900 mg in 24 hours. The serum creatinine had to be 1.0-3.0 mg/dL in women and 1.2-3.0 mg/dL in men. Patients were randomized to irbesartan 300 mg daily or amlodipine 10mg daily or placebo. The target blood pressure was 135/85mmHg in all groups. The primary outcome was a composite of doubling of baseline serum creatinine, the onset of ESKD ( defined as the initiation dialysis, renal transplant, a serum creatinine concentration of at least 6.0mg/dL, or death from any cause). The median duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a reduction of 20% of the primary composite endpoint as compared to placebo and wasv23% lower as compared to amlodipine. Overall, this trial gave us great information about the benefit of ARB use in diabetic nephropathy and dovetailed nicely with the results of the RENAAL Trial (2001) which showed that lostartan reduced the progression to ESKD of patients with diabetic nephropathy.
The IDNT Trial: Lewis, E. J., Hunsicker, L. G., Clarke, W. R., Berl, T., Pohl, M. A., Lewis, J. B., ... & Raz, I. (2001). Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New England Journal of Medicine, 345(12), 851-860.
The IDNT Trial PMID: 11565517
Useful summaries:
The REIN-2 Trial (2005)
At the time of the start of the REIN-2 Trial, it was known that ACE inhibitors were renoprotective in patients with non-diabetic proteinuria CKD, but the big question for the REIN-2 trial was if more aggressive blood pressure control would delay progression to end-stage kidney disease. Specifically, would BP reduction lower than those in the original REIN study (DBP <90mmHg) slow the progression to dialysis? The MDRD study suggested this, but had the limitation that 48% of those in the intensive BP therapy group were on an ACE inhibitor as compared to only 28% in the conventional BP therapy group. Additionally, the AASK Trial as a whole did not show a slowing CKD progression when the study population was viewed as a whole (as compared to a subgroup analysis of those with proteinuria >1g/day).
The REIN-2 Trial randomized 338 hypertensive patients with non-diabetic CKD and proteinuria to conventional or intensive BP control. Patients had to have been on an ACE for at least 6 weeks and were required to have at least 1g/day proteinuria. Patients were randomized to conventional BP control (DBP target <90mmHg) or intensive BP control (BP <130/80mmHg). The primary outcome was time to ESKD over 36 months. Patients assigned to intensive BP control had no improvement in GFR decline or progression to ESKD. Overall, this trial showed that in patients with non-diabetic proteinuria CKD on an ACE inhibitor, further reduction of BP to a target of <130/80mmHg with a dihydropyridine CCB did not slow progression of ESKD. One limitation of this trial was that the difference in SBP between conventional BP target and intensive was only 4.1mmHg. Diastolic BP was only 2.8mmHg different.
The REIN-2 Trial: Ruggenenti, P., Perna, A., Loriga, G., Ganeva, M., Ene-Iordache, B., Turturro, M., ... & Garini, G. (2005). Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. The Lancet, 365(9463), 939-946.
The REIN-2 Trial PMID: 15766995
Useful Summaries: Culleton, B., Ruggenenti, P., Perna, A., & Loriga, G. (2005). Intensified blood pressure (BP) control was not better than conventional BP control in non-diabetic chronic renal disease Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease REIN-2: multicentre, randomised controlled trial. Evidence-based Medicine, 10(5).
ASCOT-BPLA Trial (2005)
The main question for this trial was if amlodipine with or without an ACE inhibitor is more beneficial to the older combination of a beta blocker + thiazide diuretic. Remember, at this time, 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. This trial enrolled patients who were 4279 years old who either had untreated hypertension with BP >160/100mmHg, or treated hypertension with a BP >140/90mmHg. in addition, the participants had to have additional cardiovascular risk factors. The patients were randomized to start either amlodipine or atenolol to target a blood pressure <140/90mmHg (for patients without diabetes) or <130/80 (for patients with diabetes). If the blood pressure was not controlled with one agent, the arm randomized to amlodipine would have the addition of perindopril. The other arm, randomized to atenolol would have the addition bendroflumethiazide (a thiazide diuretic). Atenolol and a thiazide were chosen as comparitor drugs since these comprised the most common combination antihypertensive therapy used at the time. The primary outcome was the combined endpoint of non-fatal MI and fatal coronary heart disease (CHD). Secondary endpoints were all-cause mortality, total stroke, primary endpoint minus silent MI, all coronary events, total cardiovascular events and procedures, CV mortality, and non-fatal and fatal heart failure.
Median follow up was 5.5 years, but the trial was stopped early due to a Data Safety and Monitoring board recommendation to stop due to a reduction in all-cause mortality in the amlodipine + perindopril group. This reduction in all-cause mortality was unexpected and may have been due to confounding factors, such as smoking cessation efforts (which did not differ between the two groups). This trial did show that the amlodpine + perindopril arm lowered cardiovascular events and all-cause mortality. The primary outcome was not significantly different, possibly due to lower than expected event rate. The study was powered for the assumption of 1150 individuals to have non-fatal MI or fatal CHD. The study only observed 903 individuals with these events. Additionally, the achieved BP in the amlodipine arm was slightly lower than the atenolol arm and this may have influenced the supposed reduction in the secondary outcomes of fatal and non-fatal stroke and total cardiovascular events and procedures. Overall, this study suggested the benefit of amlodipine + perindopril and was one of the first to do so, Interestingly, this study was not directly cited in the ACCOMPLISH Trial, published a few years later, which ended up showing that the amlodipine + ACE inhibitor combination is beneficial. Even more interesting is that the primary author of the ASCOT-BPLA Trial was one of the main authors of the ACCOMPLISH Trial. Limitations of the trial design may have caused this omission as well as the ability of the trial to fully inform future BP trials. A nice review of the findings of the paper (Fuchs 2006) cast major doubt on the trial outcomes. Beta blockers have little role in BP lowering in older adults without coronary heart disease. Per the authors of this review (Fuchs 2006), the atenolol given can essentially be considered a placebo. This dovetails nicely with the fact that systolic BP was lower in the amlodipine arm. In summary, this trial could be viewed as a trial of amlodipine + perindopril vs bendroflumethiazide alone. Better trials would be needed in the future for a more fair comparison of BP medications.
The ASCOT-BPLA Trial: Dahlöf, B., Sever, P. S., Poulter, N. R., Wedel, H., Beevers, D. G., Caulfield, M., ... & Mehlsen, J. (2005). Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. The Lancet, 366(9489), 895-906.
The ASCOT-BPLA Trial PMID: 16154016
Other References: Fuchs, F. D., Gus, M., & Ribeiro, J. P. (2006). ASCOT-BPLA. The Lancet, 367(9506), 205.
Useful summaries:
The PATHWAY-2 Trial (2015)
The main question for this trial is if in patients with resistant hypertension treated with an ACEI or ARB, a CCB and a diuretic, is the addition of spironolactone superior to placebo, doxazosin or bisoprolol to control blood pressure? Before this trial, the choice of a fourth antihypertensive agent to a typical ACE inhibitor or ARB combined with a calcium channel blocker and a thiazide diuretic was empirical. Three RCTs before this study had shown that spironolactone was superior to placebo when added to existing BP medications, but no prior trial had compared spironolactone directly to other medications. The hypothesis of the investigators was that resistant hypertension was due to sodium retention. To test this hypothesis, they chose was spironolactone, a diuretic and tested it as a fourth agent against doxazosin, bisoprolol, or placebo. Doxazosin what chosen as it addressed peripheral resistance. Bisoprolol was chosen as it decreased renin and cardiac output. Since blood pressure is the product of cardiac output and peripheral arterial resistance, their choice of BP agents in the trial showcased elegant trial design. It is also an example of how basic physiology influences clinical practice in nephrology so regularly.
BLOOD PRESSURE = (CARDIAC OUTPUT x TOTAL PERIPHERAL ARTERIAL RESISTANCE)
This study screened 436 patients with uncontrolled blood pressure despite at least three months of maximally tolerated doses of three drugs including a diuretic (resistant hypertension). These drugs had to be an ACE inhibitor or ARB, a calcium channel blocker, and a diuretic. 88 patients were excluded and 335 were randomized. The randomized patients then rotated through four cycles of once daily dosing of spironolactone, doxazosin, bisoprolol, and placebo. The reason the trial says that the patients were randomized is because different permutations of the order of the sequential antihypertensives (or placebo) were randomly generated. The treatment cycles lasted for six weeks a low dose of each study drug followed by forced titration to a high dose of each study drug. If a patient could not tolerate a particular drug, they were moved to the next drug in the sequence. There was no washout period between the four cycles in the trial. The entire length of the trial was one year.The primary endpoint was average home systolic BP.
The average reduction in home systolic blood pressure by spironolactone was 8.7mmHg. This was around 4mmHg better than doxazosin or bisoprolol. The outcome of this trial is that spironolactone is the best fourth agent for BP lowering in resistant HTN. This was an important trial which greatly helps management of resistant hypertension indicating that spironolactone is the best 4th agent.
The PATHWAY-2 Trial: Williams, B., MacDonald, T. M., Morant, S., Webb, D. J., Sever, P., McInnes, G., ... & Mackenzie, I. (2015). Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. The Lancet, 386(10008), 2059-2068.
The PATHWAY-2 Trial PMID: 26414968
Useful summaries of the PATHWAY-2 Trial: Wiki Journal Club
The ACCORD BP Trial (2010)
ACCORD BP History and Rationale
The ACCORD Trial began in September of 1999. At the time of the trial start date (not publication date which occurred later during the reign of JNC 7), JNC6 was the current blood pressure guideline which recommended targeting a blood pressure of <140/90mmHg. It was known that diabetes increased the risk for CV events at every level of systolic or diastolic blood pressure, incurring increased risk at even prehypertensive BP levels. Despite this, the available trials did not support BP targets below the standard recommendation of <140/90.
The HOT and UKPDS trials had provided the strongest guidance for BP targets. The HOT Trial included a subgroup of patients with diabetes which showed a reduction in major CV events in the group targeted to a DBP <80mmHg, but the achieved BP in this group was 144/81mmHg. The UKPDS Study randomized patients with HTN and diabetes to tight BP control of <150/85mmHg or less tight BP control of <180/105mmHg. Strokes were reduced by 44%, microvascular endpoints were reduced by 37% in the tight BP control group. The achieved BP in the tight BP group in UKPDS was 144/82mmHg. On the basis of these trials and other trials, there was benefit to lowering SBP to <140mmHg, but there was no apparent benefit to more aggressive goals.
The ACCORD investigators chose to evaluate the benefit of more aggressive BP lowering. In addition, After the ACCORD Study began, JNC 7 was published in 2003 and it’s guidelines provided an even better justification for this trial. Despite a paucity of strong evidence, JNC 7 recommended a goal BP of <130/80 for patients with DM and HTN. This was somewhat unfounded and so the ACCORD investigators went out to see if there was actual benefit to this degree of BP lowering.
JNC PUBLICATION DATES
JNC 8: 2014
JNC 7: 2003
JNC 6: 1997
JNC 5: 1992
JNC 4: 1988
JNC 3: 1984
JNC 2: 1980
JNC 1: 1976
ACCORD BP DESIGN
The main question for this trial was if, in patients with T2DM at high risk for CV events, does intensive BP control (SBP <120 mmHg) reduce rates of nonfatal MI, nonfatal stroke, or CV mortality when compared to standard BP control (SBP <140 mmHg)? The ACCORD BP trial was a part of a much larger trial when tested three complementary medical treatment strategies for reducing CV morbidity and mortality in patents with type 2 diabetes. The overall ACCORD Trial was a randomized, multicenter trial which recruited 10,251 patients. It followed a double 2x2 factorial trial testing the interventions of BP targets as noted, intensive vs standard glycemic control (HbA1c <6% vs 7-7.9%), and statin+fibrate vs statin alone).
The ACCORD BP trial, however, enrolled 4733 patients and randomized them to intensive (SBP <120) vs standard (SBP <140). The reason it used a BP of <140/90 for the standard BP group was that it was based off JNC 6 guidelines when the trial was desinged (not JNC 7 guidelines which came out part way through the ACCORD Trial). BP was measured by AOBPM. Patients with a Cr >1.5 were excluded. Mean follow up was 4.7 years. Overall, intensive BP control did not reduce the primary outcome of the composite goal of nonfatal MI, nonfatal stroke, or CV mortality. In addition, the intensive BP target was associated with more serious adverse events including hypotension, bradycardia/arrhythmia, hyperkalemia , hypokalemia, elevatrion in serum creatinine. Conversely, intensive BP control did reduce the risk of the secondary outcomes of total stroke as well as nonfatal stroke.
Overall, this trial showed no benefit for intensive BP control for the primary outcome. The trial did have limitations which included possibly inadequate follow up. Longer follow-up may have detected benefit. Secondly, the event rate for primary outcomes in the standard BP group was also almost 50% lower than the expected. Lastly, there was a high prevalence of statin use among patients recurted to the overall ACCORD Trial and these patients were directed towards the ACCORD lipid trial. This reduced the power of the ACCORD BP trial and this can be seen in the wide confidence interval for the primary outcome.
CONTRIBUTION TO THE LITERATURE
This trial contributed to JNC8’s recommendation for a relaxed goal BP of <140/90 mmHg for patients with diabetes and hypertension (as compared to JNC 7 recommendation for <130/80 mmHg.
REFERENCES
The ACCORD BP Trial: ACCORD Study Group. (2010). Effects of intensive blood-pressure control in type 2 diabetes mellitus. New England Journal of Medicine, 362(17), 1575-1585.
ACCORD BP Trial PMID: 20228401
Other references: Cushman, W. C., Grimm Jr, R. H., Cutler, J. A., Evans, G. W., Capes, S., Corson, M. A., ... & Basile, J. N. (2007). Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The American journal of cardiology, 99(12), S44-S55.
Useful summaries of the ACCORD BP Trial:
The ONTARGET Trial (2008)
Losartan was the first angiotensin receptor blocker approved for use in the United States and entered the market in 1995. At that time, the benefits of ACE inhibitors was well-known, but the correct use of ARBs was still coming into play. The VALIANT Trial (2002) had shown that valsartan was non-inferior to captopril for post-MI patients complicated by heart failure or LV systolic dysfunction, but in patients with vasuclar disease, and without LV systolic dysfunction, it was unknown if there was benefit. The HOPE Trial (2000) was the trial on which the ONTARGET Trial was built. The rationale for the HOPE Trial is descriptive of the academic question of the time as there was suspicion that ACE inhibitors provided vascular benefit in prevention of myocardial infarction. The following is an excerpt from the introduction section of the HOPE Trial publication in NEJM:
“Although dyslipidemia, diabetes, smoking, and hypertension are major risk factors for cardiovascular disease, they do not fully account for the risk. Therefore, other risk factors must be identified in order to reduce mortality and morbidity even further. Epidemiologic and experimental data suggest that activation of the renin– angiotensin–aldosterone system has an important role in increasing the risk of cardiovascular events.”
The HOPE Trial evaluated rampipril vs placebo in a similar patient population to the one described later in the ONTARGET Trial. It was stopped early as it found reduced rates of death, MI, and stroke. The HOPE Trial was important because it showed cardiovascular risk reduction in patients without LV systolic dysfunction. The ONTARGET investigators wanted to see if ARBs had this same vascular protection. Theoretically, it seemed possible that an ARB could provide additional benefit as ACE inhibitors do not block all angiontension II production and and a direct receptor blockade could be beneficial. This trial set out to see if ARBs could be as beneficial in a population similar to that in the HOPE Trial. As such, the investigators of the ONTARGET Trial gathered a patient population similar to that of the HOPE Trial, utilized similar ramipril dosing, confirmed appropriate adherence rates, and aimed to have appropriate statistical power.
In short, this trial evaluated whether telmisartan was noninferior to ramipril in patients with vascular disease or high-risk diabetes for the primary composite outcome of death from CV causes, MI, stroke, or hospitalization from heart failure. It also tested if the combination of these two drugs was superior to ramipril alone. The trial was sponsored by Boehringer Ingelheim, the manufacturer of telmisartan. The trial enrolled 25,620 patients with vascular disease (coronary, peripheral, or cerebrovascular disease) or diabetes with end-organ damage. 8542 patients were assigned to receive telmisartan, 8576 were assigned to receive ramipril, and 8502 were assigned to receive a combination of both drugs. The trial first aimed to test the noninferiority of telmisartan. If this was demonstrated, then it would test the superiority of telmisartan over ramipril. Of course, the trial also assessed if the combination of the two drugs was more effective than ramipril alone. At a median follow-up of 56 months, telmisartan was found to be noninferior, but not superior to ramipril. The combination group provided no additional benefit for reduction in the primary outcome, but did result in an increased risk of hypotensive symptoms, syncope, and renal dysfunction as compared to ramipril. The telmisartan group had lower rates of cough and angioedema than ramipril, but higher rates of hypotensive symptoms. Syncope was similar among telmisartan and ramipril groups. The author’s conclusion was that in this group of patients, physicians could chose between these two medications based on physician or patient preference and a patient’s predisposition to adverse events.
The ONTARGET Trial: Ontarget Investigators. (2008). Telmisartan, ramipril, or both in patients at high risk for vascular events. New England Journal of Medicine, 358(15), 1547-1559.
ONTARGET Trial PMID: 18378520
The HOPE Trial: Yusuf, S., Sleight, P., Pogue, J. F., Bosch, J., Davies, R., & Dagenais, G. (2000). Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The New England journal of medicine, 342(3), 145-153.
HOPE Trial PMID: 10639539
Useful summaries of the ONTARGET Trial: Wiki Journal Club
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 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 valiant trial (2002)
At the time of this trial, it was recognized that heart failure and LV systolic dysfunction after myocardial infarction (MI) was very prevalent and a major source of increased mortality. By this time, ACE inhibitors had clearly been shown to improve outcomes for these patients, but it was unknown if ARBs provided the same benefit. The OPTIMAAL (OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan) trial compared losartan to captopril with MI and evidence of heart failure or LV dysfunction. All-cause mortality was not significantly different between the two groups of patient’s, but due to the large confidence intervals, the criteria for noninferiority could not be established.
The main question is if among patients in the post-MI period complicated by HF and/or LV systolic dysfunction, what is the efficacy of ARBs compared with ACE-I in improving survival? This study enrolled 14,703 patients within 10 days of an MI that was complicated by heart failure or LV systolic dysfunction. Patients were randomized to captopril, valsartan, or captopril + valsartan. The primary endpoint was all cause mortality. Secondary endpoints were CV death, MI or HF. The optimal study was a similar trial studying captopril vs losartan, but due to large confidence intervals, non-inferiority could not be established and therefore, ACE inhibitors remained first choice. The trial aimed to established superiority of valsartan vs captopril and the superiority of the combination vs captopril alone. If superiority was not established, then noninferiortity would be examined. There was around 2yrs follow up. Valsartan was noninferior to captopril. The combination of captopril and valsartan was not superior, but did increase the rates of adverse events.
This study was an important study that helped us get to the point that we can substitute ARBs for ACE inhibitors for this particular situation and helped lead to the general interchangeability of these drugs based on further studies.
The VALIANT Trial: Pfeffer, M. A., McMurray, J. J., Velazquez, E. J., Rouleau, J. L., Køber, L., Maggioni, A. P., ... & Leimberger, J. D. (2003). Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. New England Journal of Medicine, 349(20), 1893-1906.
VALIANT Trial PMID: 12921816
Useful Summaries of the VALIANT Trial: Wiki Journal Club
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 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:
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 DASH Trial (1997)
Blood pressure over the course of the DASH Trial intervention phase. The combination diet resulted in lower blood pressure than the control diet or fruits-and-vegetable diets. Blood pressure reduction took place in 2 weeks and was sustained throughout the trial.
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. As always, a growing summary of hypertension trials can be found here.
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 Syst-Eur Trial (1997)
This trial as well as summaries of other important HTN trials can be found on this website here
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.