Hypertension in Thoracic Aortic Dissection: A Meta-Analysis-Based Consideration in the Choice of Antihypertensive Agents.

Aggressive blood pressure reduction and renin–angiotensin system blockade in chronic kidney disease: time for re-evaluation?

Marc Fisher MD Kennedy Lees MD Section Editors: Hypertension is the most important modifiable risk factor for stroke.1,2 It is estimated that 25% or more of strokes may be attributable to hypertension. Because many patients with stroke have mild hypertension or prehypertension, we have shifted our focus and now think of stroke on a continuum of risk based on blood pressure (BP) level rather than on a threshold effect.3 Because high BP may not exist in isolation, a wider definition of hypertension has been proposed that also takes into account the absolute risk of cardiovascular events and associated metabolic factors or early disease markers.3 Lowering BP reduces the risk of stroke. Epidemiological studies have shown that for each 10 mm Hg lower systolic blood pressure (SBP), there is a decrease in risk of stroke of approximately one third in persons aged 60 to 79 years. This association is continuous down to levels of at least 115/75 mm Hg and is consistent across sexes, regions, stroke subtypes, and for fatal and nonfatal events.4 Lowering diastolic blood pressure (DBP) was once the main target to achieve stroke and other cardiovascular event reduction, but SBP has now become the target.3 As recently shown, even the elderly with sustained SBP elevation may gain from BP reduction in relation to less fatal or nonfatal stroke, death, and heart failure.5 Although the role of longer-term BP control to improve outcomes in patients with stroke is undisputed, BP management immediately after a stroke remains controversial. In an effort to resolve this controversy, several pilot clinical trials have been initiated. In this review, we discuss the results of some of these trials and available evidence-based guidelines for BP control in the settings of acute ischemic and hemorrhagic stroke (excluding subarachnoid hemorrhage) and …

Systemic arterial hypertension affects 72 million US adults and an additional hundreds of millions of persons worldwide.1,2 Most of these are candidates for pharmacological treatment to reduce risk of cardiovascular disease (CVD) events, based primarily on a very large body of epidemiological and intervention research in humans. Because of this high prevalence and the cardiovascular consequences of untreated or inadequately treated hypertension, the selection of drugs for initial and continuing, long-term treatment has large public health and economic implications. Fortunately, such decisions and the expert recommendations that seek to guide them can call on evidence from 4 decades of randomized multicenter clinical trials evaluating effects of treatment on clinical CVD. We summarize that evidence in this article, in approximate chronological order, and we comment on the related treatment guidelines. We close with some of the major clinical questions yet to be resolved. Response by Messerli et al p 2705 Before the current era beginning in the early 1990s of emphasis on positive-control trials, which directly compare different drug regimens, there were 3 decades of trials that compared an active regimen with placebo or, in a few cases, “usual care.” For most of this period, the mainstay of treatment was generally a thiazide-type diuretic (hereinafter called thiazides) or, to a lesser extent, a β-adrenergic blocker (termed β-blockers). With few exceptions, these trials, especially those with high statistical power and thiazide-based regimens, showed benefit for CVD outcomes.3–8 This evidence, which provided a basis for recommending thiazides or β-blockers as first-step drugs in most editions of US guidelines through 1997,9 needs to continue to be given due weight in practice and practice guidelines. The largest and most consistent benefits from the earlier trials were for stroke and (where reported) heart failure. Benefits for coronary heart disease (CHD) were less clear, …

BackgroundLocal angiotensin activity is thought to play a critical role in arterial wall homeostasis and remodeling, and impaired arterial wall integrity contributes to the pathogenesis of subarachnoid hemorrhage (SAH). Here we aimed to assess the association between pharmacologic inhibition of angiotensin‐converting enzyme and subsequent nontraumatic SAH.MethodsIn a retrospective cohort study based on Optum's Clinformatics Datamart deidentified database records (2000–2021), we included all subjects with a history of hypertension. We collected medication history, and the exposure of interest was the use of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB). The primary outcome was the subsequent development of nontraumatic SAH. Cox proportional hazard regression models were used to compare the time to SAH by type of antihypertensive treatment.ResultsA total of 7.5 million patients with hypertension were assessed. Patients on ACEI/ARBs with or without other antihypertensives (n = 4.8 million, follow‐up: 6.3 years) had lower rates of SAH compared with those on alternative antihypertensive regimens (n = 1.3 million, follow‐up: 5.7 years) (hazard ratio [HR]:0.94 [0.91–0.97]; P<0.0001), as well as compared with those on no antihypertensive medications (n = 1.4 million, follow‐up: 5.3 years) (HR:0.94 [0.91–0.97]; P = 0.0002). However, antihypertensive medications other than ACEI/ARBs were not associated with SAH risk compared with treatment by no antihypertensives (HR:1.00 [0.97–1.04]; P = 0.83). Among 8034 patients with known unruptured intracerebral aneurysms, no difference in SAH with ACEI/ARBs was observed compared to alternative antihypertensive regimens (HR:1.04 [0.95–1.13]) or no antihypertensive therapy (HR:1.06 [0.97–1.16]). Uninterrupted ACEI/ARBs use for ≥3 years reduced the risk of SAH by 23%, compared with treatment by only other hypertensives (HR:0.71 [0.68–0.74]; P<0.001).ConclusionTreatment of hypertension with ACEI/ARBs was associated with a lower risk of SAH than other types of antihypertensive agents, particularly with longer courses of therapy.

Lack of Access to Primary Care Reduces Survival Following Aortic Dissection

BackgroundRenin-angiotensin-aldosterone system (RAAS) inhibitors appear to benefit bone tissue in antihypertensive treatment. However, the association between RAAS inhibitors and bone metabolism was inconsistent.Methods and study designBased on the study of Risk Evaluation of Cancers in Chinese Diabetic Individuals(REACTION) conducted in 2011, We followed 6,252 Lanzhou residents aged 40–75 years from 2014 to 2016. Finally, 1,625 hypertension cases with complete data were included in the analysis. The study subjects were divided into four groups according to the type of antihypertensive drugs. We employed logistic or multivariate Cox proportional hazards regression to estimate the association between different antihypertensive drug use and osteoporosis, the risk of fracture, and the change in bone mineral density (BMD) level. The association of osteoporosis or the fracture risk by cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated.ResultsThe cross-sectional study showed that there was no significant association between baseline antihypertensive drugs (angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)) use and osteoporosis and fracture. During a mean follow-up of 3.4 years in the longitudinal study, there were 478 new osteoporosis cases and 76 fractures. Compared with patients without antihypertensive drug use, the hazard ratios (HRs) [95% confidence interval (CI)] for the risk of osteoporosis were 1.005(0.651,1.552) and 1.077(0.793,1.462) in ACEI or ARB use (p > 0.05). ACEI or ARB use was also not significantly associated with fracture risk (HR 1.102(0.326,3.726), 0.735(0.251,2.148), p > 0.05). Further analysis showed that the use of ACEI (HR 1.078(0.146,7.950)) or ARB (HR 1.169(0.347,3.939)) was not significantly associated with the improvement of osteoporosis (p > 0.05). In addition, the duration of RAAS inhibitors used showed no apparent correlation with the risk of osteoporosis (≤ 3 years: HR 0.872 (0.516, 1.474), > 3 years: HR 1.151 (0.574, 2.308)), nor with the improvement of osteoporosis and the risk of fracture. Meanwhile, the association mentioned above did not change compared to different RAAS inhibitors.ConclusionsThe use of RAAS inhibitors, including ACEIs and ARBs, was not significantly associated with osteoporosis, risk of fracture, or BMD change.

Background/Objectives: Angiotensin receptor–neprilysin inhibitor (ARNI) has a well-established advantage over angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy in patients (pts) with heart failure with reduced ejection fraction (HFrEF), but in pts after acute myocardial infarction (AMI) with left ventricular (LV) systolic dysfunction, the advantage of ARNI has not been clearly proven. The efficacy of ARNI is compared with that of ACEI/ARB therapy in patients with their first AMI in terms of improvement of post-infarction LV systolic function. Methods: The study was conducted as a retrospective one-center cross-sectional analysis. Overall, 1473 pts (990 M, median age 71 [64; 77]) with AMI (their first AMI, complete coronary revascularization, no prior coronary revascularization or history of HF) hospitalized in 2022–2024 were enrolled in a retrospective cross-sectional analysis. The study population was categorized into pts receiving ARNI and ACEI/ARB. Then, based on the ARNI subgroup, matching that included age, sex, and LV ejection fraction (LVEF) was performed by using the 1:1 nearest neighbor method without returning. Finally, two groups (ARNI vs. ACEI/ARB) of 30 pts were obtained and analyzed at baseline and at a 6-week follow-up. The improvement of post-infarction LV systolic function was obtained in terms of LVEF, ΔLVEF, and relative ΔLVEF values (ΔLVEF/baseline LVEF). Results: The comparison of baseline characteristics revealed borderline lower initial LVEF (30 vs. 36%, p = 0.076) and a higher frequency of SGLT-2 inhibitor use (70% vs. 36.7%, p = 0.01) in the ARNI subgroup. At the 6-week follow-up, in both subgroups, a significant improvement in the median LVEF values was achieved—from a median LVEF value of 30% (27.3; 38) to 37% (30; 43; p = 0.0008) in the ARNI subgroup and from a median LVEF value of 36% (33; 39) to 45% (42; 52; p < 0.0001) in the ACEI/ARB subgroup. The median ΔLVEF in the ACEI/ARB subgroup was higher [10% (6; 12)] than in the ARNI subgroup [6% (2; 10.25), p = 0.018]. Similarly, the median relative ΔLVEF was higher in the ACEI/ARB subgroup [30% (15.4; 40)] than in the ARNI group [17.5% (7; 31.9), p = 0.047]. The vast majority of patients, particularly in the ARNI group (99.7%), were treated with the lowest available dose of the drug. Conclusions: Our current experience in ARNI therapy after AMI is promising; however, it is limited to a small group of patients with severe impairment of LV systolic function. Regardless of the significant improvement in the baseline LVEF observed in patients receiving both ACEI/ARB and ARNI at the 6-week follow-up, the absolute and relative increases in the LVEF were higher in subjects treated with ACEI/ARB. However, the clinical benefits of ARNI therapy may emerge more gradually, and its advantages could become more apparent over a longer follow-up period. The clinical efficacy of early use of ARNI in the setting of AMI needs further evaluation.

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

To investigate the current status of blood pressure control rate and the use of antihypertensive drugs in elderly patients with coronary heart disease, diabetes mellitus and hypertension. The elderly coronary heart disease patients with diabetes mellitus and hypertension (≥ 60 years old) were recruited from 165 hospitals in 21 provinces or cities across China from April to July 2011 in this multicenter, non-intervention and cross-sectional survey. The current status of blood pressure control rate in different antihypertensive target value, methods for application in antihypertensive drugs and standardized treatment recommended by guideline were investigated in the survey. 1 379 cases were eventually selected from the total 7 962 elderly patients (accounted for 17.3%). (1) The blood pressure control rate was 17.1% for antihypertensive target value (<130/80 mmHg); the control rate for 140/80 mmHg was 27.5%; the control rate for 140/90 mmHg was 39.6%; the success rate for 150/90 mmHg were 51.7%; control rate of elderly patient (≥ 70 years old) gradually increased with increasing of age; success rate of elderly patient (≥ 85 years old) was the highest, whereas control rate of elderly patient aged 71-71 years old was lowest; success rate for male patients was close to female patients, and success rate for men were slightly higher than those in women; (2) 1 347 cases had clear medication history (32 cases were missed) in the survey, 1 317 effective cases received antihypertensive therapy (effective rate was 97.8%, 1 317/1 347); the more commonly used drugs were angiotensin receptor blockers (ARB) /angiotensin converting enzyme inhibitors (ACEI) (usage rate was 76.8%), followed by dihydropyridine calcium channel blockers (CCB) (65.5%), β-blockers (usage rate was 44.6%), thiazide diuretics (26.3%) respectively; (3) combinations of two drugs was the most common way in antihypertensive medication (accounted for 41.2%), three drugs or more was 28.9%, and single drug was 23.9%; CCB was the commonly used single drug (accounted for 8.8%); combinations of CCB and ARB were the most common way in combination of two drugs(11.7%), CCB combined with ARB and β-blockers was frequently used in combination of three drugs or more (9.2%); (4) 987 cases received standardized treatment recommended by guideline (accounted for 76.6%); the percentage of standardized usage in combinations of two drugs was 71.9%, the percentage of standard usage in combinations of three drugs or more was 66.1%. The percentage of antihypertensive therapy is high, however, the overall blood pressure control rate is low. ACEI /ARB are the major drugs in antihypertensive medication, diuretic drugs are now rarely used; combined medication is the common method of antihypertensive therapy; the consciousness following the guidelines has improved, but still need to be strengthened.

Objective To summarise the features and treatments of hypertension in elderly patients with Stanford B aortic dissection. Methods Retrospectively analysed the features and treatments of hypertension between the elderly patients (≥ 60 years, n = 91) and the non-elderly patients (n = 187) who were suffered from Stanford B aortic dissection and hospitalised between April 2002 and July 2011. Results The proportion of male in elderly group was higher than that in non-elderly group (P &lt; 0.05). Smoking was similarly common in both groups. The proportions of patients accompanied with diabetes mellitus, hyperlipidemia, hypertension and renal inadequacy had no statistics differences between two groups. Coronary artery disease, atherosclerotic ulcer and cardiac insufficiency were more often seen in elderly group (P &lt; 0.05). Histories of hypertension were more often given while the first-time diagnosis of hypertension were made less frequently in elderly group (P &lt; 0.05). Isolated systolic hypertensions were seen with greater frequency in the elderly group (P &lt; 0.05). The courses of hypertension were longer in the elderly group than those in the non-elderly group (P &lt; 0.05). The proportions of family history of hypertension and hypertension of grade 1, grade 2 and grade 3 had no statistics differences between two groups. The highest systolic pressures, diastolic pressures and pulse pressures of the patients on admission and the average systolic pressures, diastolic pressures and pulse pressures after treatments had no statistics differences between two groups. The combined treatments were applied frequently in both groups. The usages of intravenous drugs had no differences between two groups. Combinations of 2 antihypertensive drugs were more often used in the elderly group than those in the non-elderly group (P &lt; 0.05). Combinations of 3 antihypertensive drugs were used most frequently in both groups. Calcium-channel blocker, β-receptor blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, diureticum, angiotensin receptor blocker+diureticum and α1 + β receptor blocker were adopted in turn as hypotensive drugs in elderly group. α1 + β receptor blocker was less used in the elderly group (P &lt; 0.05). Conclusions The awareness rate of hypertension was higher and the highest blood pressures on admission were lower in elderly patients with Stanford B aortic dissection. The types of anti-hypertension drugs were less and α1 + β receptor blocker was less used in the elderly group.

When used as first-line agents for the treatment of hypertension, thiazides and thiazide-like drugs likely do not change total mortality and likely decrease some morbidity outcomes such as cardiovascular events and withdrawals due to adverse effects, when compared to beta-blockers, calcium channel blockers, ACE inhibitors, and alpha-blockers.

Obesity hypertension is an ongoing pandemic. The first-line medications to treat this condition are still subject to debate. We compared diuretics, calcium-channel blockers (CCB), beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) as an initial antihypertensive therapy for prevention of cardiovascular morbimortality of hypertensive individuals who are overweight or obese. We conducted a search of the literature for randomized clinical trials in which at least 50% of the participants were overweight or obese. The primary outcomes were all-cause mortality, cardiovascular mortality, acute myocardial infarction (MI), heart failure (HF), stroke, or end-stage renal disease. Our search yielded 16 randomized studies. Comparisons of two classes of drugs with at least two studies indicated that (1) CCB and ACEI increased the risk of HF [relative risk (RR) = 2.26; 95% confidence interval (CI) 1.16-4.40] and stroke [hazard ratio (HR) = 1.13; 1.00-1.26]), respectively, compared to diuretics; and (2) CCB showed a reduction in stroke (HR = 0.77; 0.66-0.89) and total mortality (HR = 0.94; 0.87-1.01) compared to the BB atenolol. Comparisons of two classes of antihypertensive medications with only one study showed that the risk of MI was higher with ARB valsartan versus CCB (HR = 1.19; 95% CI 1.02-1.38, p = 0.02). In contrast, losartan lowered the risk of a composite cardiovascular outcome compared to atenolol (HR = 0.87; 95% CI 0.77-0.98, p = 0.02). In hypertensive subjects with excess weight, diuretics are more effective for preventing HF and stroke than CCB and ACEI, respectively. CCB are a good first-line choice for prevention of cardiovascular disease, except HF.

Over the past 5 years, numerous hypertension treatment trials have been completed and reported.1-8 A majority of these trials were initiated to distinguish one therapy from another in reducing cardiovascular (CV) events. Some were blinded and appropriately randomized prospective trials; others were unblinded or prospective cohort studies. Various populations have been studied, and results have differed. Statistical manipulations have often been carried out to prove a point if trial results were different than the investigators had anticipated. An ongoing question remains: “What really matters in determining therapy?” Is it the lowering of blood pressure (BP) that reduces CV events, or does the use of specific medications account for differing results? A meta-analysis of the clinical trials has determined that it is the degree of BP lowering that makes the major difference in outcome, and not specific medical therapy.9 Many individual trials appear to confirm this conclusion. For example, the Verapamil in Hypertension Atherosclerosis Study (VHAS)10 reported no difference in outcome between a diuretic and verapamil. The Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE)8 study reported no differences between a verapamil-based treatment and usual care, i.e., a diuretic plus a β blocker and other drugs, and the United Kingdom Prospective Diabetes Study (UKPDS)11 in type 2 diabetics reported no difference in outcome between a β-blocker-based and an angiotensin-converting enzyme inhibitor (ACEI)-based treatment program if Bps were lowered to an equivalent degree. In the latter study, which included an 8.5-year follow-up of more than 1100 patients, a difference of only 10/5 mm Hg accounted for a significant decrease in macrovascular and microvascular CV events in diabetics in the group of patients who achieved the lower levels of BP.11 In the Swedish Trial in Old Patients with Hypertension (STOP-2) study,12 both systolic and diastolic Bps were reduced to an equivalent degree with calcium channel blockers (CCBs) and ACEIs compared with diuretics and β blockers. There was also no significant difference in overall outcomes. In this study, however, patients on ACEIs had fewer myocardial infarctions (MIs) and less congestive heart failure than patients receiving a CCB. This finding had also been noted in several other smaller studies when a CCB-based regimen was compared with an ACEI-based treatment program.13, 14 In the Blood Pressure Lowering Treatment Trialists' Collaboration meta-analysis, however, these differences were not noted,9 and more recent studies have reported that CCB-based therapy appears to result in CV outcomes similar to those with ACEI- or angiotensin receptor blocker (ARB)-based regimens. It appears, therefore, that abundant data confirm that BP lowering accounts for most of the benefit noted in the clinical trials. In some high-risk patients, however, results have been somewhat different. In the Heart Outcomes Prevention Evaluation (HOPE),7 the Irbesartan Diabetic Nephropathy Trial (IDNT),15 the Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients (IRMA) study,16 the Reduction in Endpoints in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL),6 and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)5 studies, the use of an ACEI or angiotensin receptor blocker (ARB), usually given with a diuretic, reduced CV events to a greater degree than a regimen that did not include these medications. In these studies, it appeared that specific medications made a difference in CV event outcome, especially in patients with diabetes and renal disease. Thus, while most trial results confirm the conclusions of the meta-analyses, others indicate that there are instances where specific medications may be more effective than others. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),1 a randomized, double-blind, multicenter, non-industry-sponsored clinical trial, reported that >60% of hypertensive patients with a mean age of 67 years could be controlled with Bps lower than 140/90 mm Hg if goal Bps were vigorously pursued.17 Primary outcomes (fatal and nonfatal coronary heart disease) showed no difference when a diuretic (chlorthalidone)-based treatment regimen was compared with an ACEI (lisinopril) or a CCB (amlodipine)-based program. When further analyses were done, however, diuretic-treated patients had fewer strokes than ACEI subjects and fewer episodes of heart failure compared with either ACEI- or CCB-treated patients. Some investigators were quick to note that black patients and patients over 65 years of age experienced a greater BP decrease on the diuretic than with other medications, especially when the ACEI was compared with the diuretic. A 4-mm Hg systolic BP difference was noted in black subjects; a 3-mm Hg systolic BP difference was noted in the over-65 group. This may have accounted for at least some of the significant differences in stroke outcome. Specific actions of one medication may, therefore, not have accounted for differences in benefit between groups. In this trial, as in all the others, multiple medications were necessary to achieve goal Bps in a majority of patients. The ALLHAT investigators concluded that a diuretic should be the first-choice drug in most patients but also concluded that a majority of hypertensive patients required more than one drug to achieve goal Bps. The Second Australian National Blood Pressure study (ANBP-2),2 which was not blinded, compared an ACEI-based to a diuretic-based regimen in elderly patients over 5 years. The ACEI-treated patients experienced a marginally better long-term outcome; the benefit, however, was noted only in male patients. Some physicians concluded that the ASNBP-2 results, which were different from ALLHAT, should be the ones to guide therapy—that an ACEI-based treatment program was more beneficial in reducing CV events than a diuretic-based regimen. In the Valsartan Antihypertension Long-Term Evaluation (VALUE),3 Bps were lowered, especially during the first 6 months, to a greater degree with amlodipine than an ARB (valsartan). The occurrence of Mis was lower in the CCB group. Statistical calculations were done to demonstrate that in people with the same achieved BP there was no difference in outcome, but the question of whether it was the achieved BP or a specific treatment that made the difference was not settled. VALUE, like ALLHAT and ASNBP-2, was a trial of multiple-drug therapy and did not completely settle the question of one medication's superiority over another in reducing CV events. The LIFE study,5 which compared the results of an ARB (losartan)- to a β-blocker (atenolol)-based program in hypertensives with left ventricular hypertrophy, demonstrated that strokes were significantly reduced in the ARB group despite essentially similar Bps in both groups at the end of the trial. This trial suggested that specific therapy did make a difference in outcome, at least in some patient subgroups. It was not surprising that outcome was better with therapy other than a β blocker; this had been demonstrated many years ago in the Medical Research Council trial18 in the elderly. When a diuretic was compared with a β blocker and a placebo, the use of a diuretic resulted in a significantly greater decrease in coronary heart disease events compared with the β blocker, but in this trial BP was reduced to a greater degree and in more patients with the diuretic. Other studies, such as RENAAL6 and HOPE,7 suggest that there is some difference in outcome with certain agents compared with other medications with equivalent decreases in BP. But in some of these trials, especially the HOPE trial, there is still a question of whether or not it was BP lowering or medication that made the difference in outcome. Finally, the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial,4 which included 77% males and more than 90% Caucasians, concluded that a CCB-based (plus an ACEI) regimen reduced mortality and strokes more than a β-blocker-based (plus a diuretic) program. But, as in the ALLHAT trial, the primary outcome (MI) was similar with both therapies.4, 19 Basically, ASCOT compared a CCB titrated upward to a β blocker titrated upward regimen within the first few months of the study. There was a difference of 5.9/2 mm Hg in BP control in the first few months; this may conceivably have resulted in the better outcome with the CCB. The ASCOT investigators concluded that, based on secondary end points, national guidelines should be changed and that so-called “contemporary” therapy (i.e., CCBs and ACEIs) was superior to older therapy (β blockers and diuretics). The results regarding the use of β blockers as initial therapy may be applicable to elderly Caucasian males but, based on ASCOT, cannot be applied to other gender and ethnic groups. It is also inappropriate, based on the results of ALLHAT and other trials in which diuretics were used as initial therapy, to suggest that the current recommendations for use of these agents be changed. The ASCOT results should not influence guidelines such as those of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)20 that suggested diuretics as initial therapy in most patients and suggested as early as 1998 in JNC VI21 that β blocker monotherapy was not preferred initial therapy in the elderly. ASCOT has confirmed, however, what other trials had reported—multiple medications are necessary to reduce BP. Thus, there are meta-analyses that indicate that it is the BP level that makes the difference in outcome, but also some confusion from several of the trials that suggest specific benefits of various medications over and above the effects of BP lowering. When the data are carefully considered, two conclusions, which may actually not be confusing, can be reached22: 1) the “my drug is better than your drug” argument may be moot—multiple medications are necessary to achieve goal Bps in most cases—and none of the recent trials which have been so highly promoted were trials of monotherapy; and 2) most of the benefit achieved in the treatment trials results from more effective BP control, with exceptions in the cases of patients with diabetes or renal disease. An additional confusing message relates to the occurrence of NOD as a result of treatment in some hypertensive patients. This has recently been reviewed.23, 24 It is well known that diabetes is more common in hypertensives than in normotensives.25 There is, however, a <1% increase in NOD with diuretics and β blockers in placebo-controlled hypertensive treatment trials. In chart reviews, no difference has been found in NOD among diuretics, ACEIs, and CCBs, but an increase has been noted with β blockers.25, 26 In comparative trials, a 1%–3.5% absolute increase in NOD has been reported with a diureticbased compared with an ACEI-based treatment program and about a 1% increase when compared with CCBs.27 The clinical significance of this finding has been questioned; further studies are needed to decide whether or not CV outcome is affected. Data are conflicting. One study with a small number of events suggests that NOD has a similar prognosis as pretreatment diabetes; another does not.28, 29 Both studies report that, while there appears to be a relationship between NOD and the use of diureticbased treatments, there does not appear to be an independent relationship to CV outcome. At present, the data do not indicate that the findings of NOD should lead to a change in the JNC 7 recommendation for diuretics as initial therapy for most patients. The results of some of the recent trials and the NOD data do suggest, however, that the use of β blockers (without vasodilator or α-blocking actions) may not be preferred as initial antihypertensive therapy, especially in obese patients or subjects with findings of the metabolic syndrome. These medications are indicated, however, in patients with angina, heart failure, and post-MI. They should also continue to be used in combination with a diuretic, if necessary, to reduce BP to goal levels.27 Despite all of the expense and effort expended to convince physicians that one therapy is superior to another, the bottom line remains: reduce the BP to as low as possible without interfering with the enjoyment of life, and CV outcome will improve. The choice of medication, with the exception of certain subgroups of patients, appears to be less important than achieving goal BP; medications with differing actions will be necessary in most patients to achieve goal Bps.

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) compared in >30 000 high-risk hypertensive patients the effects on coronary heart disease of 3 treatment strategies: (1) based on the diuretic chlorthalidone, (2) the calcium-channel blocker (CCB) amlodipine, and (3) the angiotensin converting-enzyme (ACE) inhibitor lisinopril, respectively.1 Sponsored by the National Heart, Lung, and Blood Institute, ALLHAT stands out because no differences occurred in the incidence of the primary end point that consisted of the combination of fatal coronary heart disease and acute myocardial infarction.1 Not surprisingly, the attention of the ALLHAT consortium shifted to secondary end points, such as stroke, or to loosely defined2 components of secondary end points, such as heart failure. At the end of the line, the ALLHAT investigators based their main conclusions on events that, at the initiation of the trial, they regarded as “soft data that will at best confirm or supplement the primary endpoint.”3 More importantly, what was not identical in the 3 treatment groups was the on-treatment blood pressure despite vigorous attempts to titrate and combine the study medications to achieve a blood pressure of <140 mm Hg systolic and 90 mm Hg diastolic.1 These salient features of ALLHAT should be kept in mind whenever one attempts to interpret the findings of this landmark trial. In this issue of Hypertension , Leenen et al4 published a post hoc analysis, in which they made a direct comparison of cardiovascular and other outcomes among the 18 102 ALLHAT participants randomly assigned to amlodipine or lisinopril. In line with previous reports,1 the incidence of the primary coronary end point and total and cardiovascular mortality were similar in both groups. However, the patients randomly assigned to lisinopril experienced higher risks of stroke, combined cardiovascular disease, gastrointestinal bleeding, …

Recent heart failure (HF) guidelines have re-classified HF patients with left ventricular ejection fraction (LVEF) between 41% and 49% as HF with mildly reduced ejection fraction (HFmrEF). HFmrEF treatment is often considered a grey zone as no randomized controlled trials (RCTs) were conducted exclusively on these patients. A network meta-analysis (NMA) was performed to compare treatment effect of mineralocorticoid receptor antagonists (MRA), angiotensin receptor neprilysin inhibitor (ARNi), angiotensin receptor blockers (ARB), angiotensin-converting-enzyme inhibitors (ACEi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and beta-blockers (BB) in HFmrEF cardiovascular (CV) outcomes. RCTs sub-analyses evaluating the efficacy of pharmacological treatment in HFmrEF patients were searched. Hazard ratios (HRs) and their variance were extracted from each RCT for (i) composite of CV death or HF hospitalizations, (ii) CV death, and (iii) HF hospitalizations. A random-effects NMA was performed to compare and assess the treatment efficiency. Six RCTs with subgroup analysis according to participants' ejection fraction, a patient-level pooled meta-analysis of two RCTs, and an individual patient-level analysis of eleven BB RCTs were included, totalling 7966 patients. To our primary endpoint, SGLT2i vs. placebo was the only comparison with significant results, with a 19% risk reduction in the composite of CV death or HF hospitalizations [HR 0.81, 95% confidence interval (CI) 0.67-0.98]. In HF hospitalizations, the impact of the pharmacological therapies was more notorious, and ARNi reduced in 40% the risk of HF hospitalizations (HR 0.60, 95% CI 0.39-0.92), SGLT2i in 26% (HR 0.74, 95% CI 0.59-0.93) and renin-angiotensin system inhibition (RASi) with ARB and ACEi in 28% (HR 0.72, 95% CI 0.53-0.98). Although BBs were globally less beneficial, they were the only class that supported a reduced risk of CV death (HR vs. placebo: 0.48, 95% CI 0.24-0.95). We did not observe a statistically significant difference in any comparison between active treatments. There was a sound reduction with ARNi on the primary endpoint (HR vs. BB: 0.81, 95% CI 0.47-1.41; HR vs. MRA 0.94, 95% CI 0.53-1.66) and on HF hospitalizations (HR vs. RASi 0.83, 95% CI 0.62-1.11; HR vs. SGLT2i 0.80, 95% CI 0.50-1.30). In addition to SGLT2i, pharmacological treatment recommended for HF with reduced LVEF, namely, ARNi, MRA, and BB, can also be effective in HFmrEF. This NMA did not show significant superiority over any pharmacological class.