Franz H. Messerli

Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?

Context Experts debate the consequences of excessive lowering of diastolic pressure in patients with hypertension and coronary artery disease. Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease. The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infarction, with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg, that is, the lower the diastolic pressure, the higher the risk. Cautions The study examined associations between blood pressure and outcomes; it could not prove that the antihypertensive therapy that lowered diastolic pressure too much caused the adverse outcomes. The Editors For 2 decades, the hypertension literature has been haunted by the phenomenon of a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure (J-curve). Indeed, several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications (1-13). After doing a review and meta-analysis of pertinent studies, Farnett and colleagues (14) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure, there was a consistent J-shaped relationship for cardiac events and diastolic pressure. These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease. These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) (15), which stated that the relationship between pressure and risk was strong, continuous, independent, predictive and etiologically significant. Within the past decade, the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients (16-30). Not surprisingly, arguments regarding whether a J-curve could be clinically significant have become somewhat contentious. That is, some rely on evidence that on-treatment diastolic pressure below 70 mm Hg does not increase risk for cardiovascular disease and thus deny an impairment of vital organ perfusion within the usual values achievable by antihypertensive treatment. Others, however, consider the J-curve a more real possibility, particularly for the heart. In contrast to other organs, the heart is perfused mostly during diastole and thus could be more vulnerable to diastolic pressure reduction. If a J-curve did exist, it should be most evident in patients with limited coronary perfusion, in other words, in those with manifest coronary artery disease (CAD). Optimal blood pressure in patients with hypertension and CAD remains controversial because few randomized clinical trials have been done in this population (31, 32). The International Verapamil-Trandolapril Study (INVEST) (33), a randomized trial, evaluated more than 22000 patients with CAD and hypertension. This patient profile, together with unprecedented levels of blood pressure control, provided a unique opportunity to critically investigate the hypothesis that the risk for CAD would increase with an excessive decrease in diastolic pressure. Methods Study Design and Intervention The INVEST design, methods, and principal results have been previously published (33). The trial used an open design with blinded end point assessment. In brief, clinically stable patients with CAD and hypertension were randomly assigned to a verapamil sustained-releasebased or atenolol-based strategy. Patients with previous myocardial infarction (MI) within 3 months of enrollment or class IV or V congestive heart failure were excluded. Blood pressure goals were based on JNC VI (systolic pressure <140 mm Hg and diastolic pressure <90 mm Hg or systolic pressure <130 mm Hg and diastolic pressure <85 mm Hg in patients with diabetes or renal impairment) (15). The addition of trandolapril or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment. Documented CAD was defined as any of the following: remote (3 months before enrollment) confirmed MI, coronary angiography showing more than 50% narrowing of at least 1 major coronary artery, diagnosis of classic angina pectoris, or concordant abnormalities on 2 different signals (electrocardiography, echocardiography, or radionuclide scans) from stress test findings concordant for ischemia (for example, ST-segment depression or perfusion defects on radionuclide scanning or wall-motion abnormalities on echocardiography or radionuclide scanning). Patient Monitoring and Follow-up Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled. Patients were assessed for response to treatment, symptoms, treatment adherence, and adverse effects at each visit and at the end of the study as detailed elsewhere (33). Patient follow-up was complete when we received a final assessment form through the online data system or a death report. The Internet-based electronic data collection method used in INVEST did not accept the entry until all required fields were complete. Blood pressure was measured by using a standard mercury sphygmomanometer with an appropriately sized cuff applied to the upper nondominant arm at heart level. By auscultation at the brachial artery, systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound. Blood pressure was measured twice, at least 2 minutes apart, and the measurements were averaged. Study Outcomes The primary outcome was the first occurrence of all-cause death, nonfatal MI, or nonfatal stroke by intention-to-treat analysis. The MI and stroke definitions are detailed elsewhere (34). These 3 components individually were the main secondary outcomes. For this analysis, additional outcomes included fatal and nonfatal MI, fatal and nonfatal stroke, and average on-treatment blood pressure before outcome or censoring. Ascertainment and blinded adjudication of outcomes were described previously (32). Follow-up data were available for 22008 (97.5%) patients. Statistical Analysis The main conclusions of INVEST were that the 2 treatment strategies were equivalent with respect to the primary outcome, main secondary outcomes, and on-treatment systolic and diastolic pressures. Thus, data for all enrolled patients were combined and included in these analyses following the intention-to-treat principle. A P value of 0.05 or less was considered statistically significant. Patients without a primary outcome event were censored at their latest follow-up visit. Average follow-up systolic and diastolic pressures were calculated for each patient by using all post-baseline results, up to the date of primary outcome or censoring. The baseline value was substituted for patients with no post-baseline data (n= 1154). In this exploratory analysis, the proportions of patients were pooled by 10mm Hg strata of average follow-up systolic pressure, and the distribution of primary outcome event rate was evaluated to determine whether the relationship was linear. A similar presentation was prepared for diastolic pressure. Because the frequency distributions seemed consistent with a quadratic curve, a quadratic Cox proportional hazards model was formed for the time to primary outcome for each blood pressure variable, with factors for blood pressure and blood pressure squared. Similarly, the relationship between each 10mm Hg stratum of average systolic pressure and diastolic pressure and all-cause death, fatal and nonfatal MI, and fatal and nonfatal stroke was evaluated. For the time to primary outcome, a second model was fitted, adjusting for the following baseline covariates: age (10-year increments), sex, race and ethnicity (white, Asian, black, Hispanic, multiracial, or other), previous MI, heart failure (classes I to III), body mass index in increments of 5 kg/m2, U.S. residency, renal impairment, peripheral vascular disease, left ventricular hypertrophy, smoking history, coronary revascularization, dyslipidemia, stroke or transient ischemic attack, angina pectoris, arrhythmia, diabetes, cancer, aspirin use, and average systolic pressure or diastolic pressure and systolic pressure squared or diastolic pressure squared. To identify clinically relevant interactions between the J-shaped curve and baseline diastolic pressure, demographic characteristics, and comorbid conditions for the primary outcome, a 2-step procedure was used. First, baseline covariates were tested individually by adding the variable and 2 interaction terms (variablediastolic pressure and variable[diastolic pressure squared]) to the Cox proportional hazards model. Variables included were age older than 70 years, sex, previous MI, heart failure (classes I to III), previous stroke or transient ischemic attack, diabetes, cancer, renal impairment, hypercholesterolemia, peripheral vascular disease, smoking history, U.S. residency, body mass index greater than 29 kg/m2 (mean baseline body mass index), and diastolic pressure greater than 86 mm Hg (mean baseline diastolic pressure). The change in log likelihood was used to assess the significance of simultaneously adding the 2 interaction terms. The second step in identifying clinically relevant interactions between the J-shaped curve and baseline covariates was to plot the hazard ratios for the primary outcome versus diastolic pressure in the pr

Hypertension and sudden death: Increased ventricular ectopic activity in left ventricular hypertrophy

The present study was designed to detect and quantify cardiac arrhythmias in hypertensive patients with left ventricular hypertrophy. Continuous ambulatory electrocardiographic tracings and arterial pressure were recorded for 24 hours in 14 normotensive subjects, 10 patients with established essential hypertension without left ventricular hypertrophy, and 16 hypertensive patients with left ventricular hypertrophy by electrocardiographic criteria. Urinary excretion of norepinephrine was simultaneously measured over four successive four-hour and one eight-hour period. Patients with left ventricular hypertrophy had significantly more ventricular (but not atrial) premature contractions than those without left ventricular hypertrophy or than normotensive subjects. Five patients with left ventricular hypertrophy had episodes of more than 30 premature ventricular contractions per minute. Higher-grade ventricular ectopic activity such as coupled premature ventricular contractions was seen in two, and multifocal premature ventricular contractions were seen in three in the group with left ventricular hypertrophy. No difference in urinary catecholamine excretion rates among the three groups was seen. Left ventricular hypertrophy has been shown to be an independent risk factor for sudden death and acute myocardial infarction. Electrocardiographic monitoring of patients with left ventricular hypertrophy allows identification of those who have the highest risk and, therefore, require the most aggressive therapeutic intervention.

Serum Uric Acid in Essential Hypertension: An Indicator of Renal Vascular Involvement

We measured glomerular filtration rate, renal and systemic hemodynamics, and intravascular volume in normotensive subjects and in borderline and established essential hypertensive patients classified according to serum uric acid level. Renal blood flow was lower and renal vascular and total peripheral resistances were increased in patients with high uric acid levels (p < 0.02). Serum uric acid concentration correlated inversely with renal blood flow/m2 body surface area (r = -0.45, p < 0.001) and directly with renal vascular (r = 0.41, p < 0.001) and total (r = 0.38, p < 0.001) resistance. Cardiac output, heart rate, and intravascular volume as well as glomerular filtration rate showed no uric-acid-department pattern. Mild asymptomatic hyperuricemia, therefore, was associated with decreased renal blood flow without affecting glomerular filtration rate. Increased renal vascular and total peripheral resistances reflecting renal and systemic hypertensive vascular disease paralleled the rising serum uric acid levels. These data suggest that heretofore unexplained hyperuricemia in patients with essential hypertension most likely reflects early renal vascular involvement, specially, nephrosclerosis.

ESSENTIAL HYPERTENSION IN THE ELDERLY: HAEMODYNAMICS, INTRAVASCULAR VOLUME, PLASMA RENIN ACTIVITY, AND CIRCULATING CATECHOLAMINE LEVELS

In an attempt to dissociate the cardiovascular adaptations to high blood pressure from those of ageing, 30 patients with established essential hypertension aged over 65 years were matched for mean arterial pressure, race, sex, height, and weight with 30 patients younger than 42 years. Cardiac output, heart rate, stroke volume, intravascular volume, renal blood flow, and plasma renin activity were significantly lower in the elderly, whereas total peripheral (and renal vascular) resistance, left ventricular posterior wall and septal thicknesses, and left ventricular mass were higher. Intravascular volume correlated inversely with total peripheral resistance in both groups and in all patients. Pathophysiological findings of essential hypertension in the elderly are characterised by a hypertrophied heart of the concentric type with a low cardiac output resulting from a smaller stroke volume and a slower heart rate. Renal blood flow is disproportionally reduced and total peripheral and renal vascular resistance elevated.

Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis

BACKGROUND American College of Cardiology and American Heart Association (ACC/AHA) guidelines on perioperative assessment recommend perioperative beta blockers for non-cardiac surgery, although results of some clinical trials seem not to support this recommendation. We aimed to critically review the evidence to assess the use of perioperative beta blockers in patients having non-cardiac surgery. METHODS We searched Pubmed and Embase for randomised controlled trials investigating the use of beta blockers in non-cardiac surgery. We extracted data for 30-day all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, heart failure, and myocardial ischaemia, safety outcomes of perioperative bradycardia, hypotension, and bronchospasm. FINDINGS 33 trials included 12 306 patients. beta blockers were not associated with any significant reduction in the risk of all-cause mortality, cardiovascular mortality, or heart failure, but were associated with a decrease (odds ratio [OR] 0.65, 95% CI 0.54-0.79) in non-fatal myocardial infarction (number needed to treat [NNT] 63) and decrease (OR 0.36, 0.26-0.50) in myocardial ischaemia (NNT 16) at the expense of an increase (OR 2.01, 1.27-3.68) in non-fatal strokes (number needed to harm [NNH] 293). The beneficial effects were driven mainly by trials with high risk of bias. For the safety outcomes, beta blockers were associated with a high risk of perioperative bradycardia requiring treatment (NNH 22), and perioperative hypotension requiring treatment (NNH 17). We recorded no increased risk of bronchospasm. INTERPRETATION Evidence does not support the use of beta-blocker therapy for the prevention of perioperative clinical outcomes in patients having non-cardiac surgery. The ACC/AHA guidelines committee should soften their advocacy for this intervention until conclusive evidence is available.

Dimorphic Cardiac Adaptation to Obesity and Arterial Hypertension

Cardiovascular function and structure were evaluated by M-mode echocardiography and systemic hemodynamics in paired lean and obese patients, either hypertensive or normotensive. Compared to lean patients, obese patients had greater left atrial (p less than 0.0001), ventricular (p less than 0.001), and aortic root (p less than 0.002) diameters; posterior and septal wall thickness (p less than 0.001); and ventricular mass, cardiac output, stroke volume, and stroke work (all p less than 0.0001). Hypertensive patients had increased posterior wall thickness, end diastolic wall stress, stroke work (p less than 0.01), and a lower radius to posterior wall thickness ratio indicating concentric hypertrophy (p less than 0.001) when compared to normotensive patients. Cardiac adaptation to obesity consists of left ventricular dilatation and hypertrophy (eccentric hypertrophy) irrespective of arterial pressure levels. In contrast, essential hypertension solely produces concentric hypertrophy. Both obesity and hypertension increase left ventricular stroke work by disparate hemodynamic mechanisms; their presence in the same patient will tax the heart and increase the long-term risk of congestive failure.

Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trials.

Background— Most guidelines for treatment of hypertension recommend a blood pressure (BP) goal of <140/90 mm Hg, and a more aggressive goal of <130/80 mm Hg for patients with diabetes mellitus. However, in the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a lower BP was not beneficial. The optimal BP target in subjects with diabetes mellitus or those with impaired fasting glucose/glucose tolerance is therefore not well defined. Methods and Results— We performed PUBMED, EMBASE, and CENTRAL searches for randomized clinical trials from 1965 through October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of ⩽135 mm Hg in the intensive BP control group and ⩽140 mm Hg in the standard BP control group, had a follow-up of at least 1 year, and evaluated macrovascular or microvascular events. We identified 13 randomized clinical trials enrolling 37 736 participants. Intensive BP control was associated with a 10% reduction in all-cause mortality (odds ratio, 0.90; 95% confidence interval, 0.83 to 0.98), a 17% reduction in stroke, and a 20% increase in serious adverse effects, but with similar outcomes for other macrovascular and microvascular (cardiac, renal, and retinal) events compared with standard BP control. The results were similar in a sensitivity analysis using a bayesian random-effects model. More intensive BP control (⩽130 mm Hg) was associated with a greater reduction in stroke, but did not reduce other events. Meta–regression analysis showed continued risk reduction for stroke to a systolic BP of <120 mm Hg. However, at levels <130 mm Hg, there was a 40% increase in serious adverse events with no benefit for other outcomes. Conclusions— The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable. However, with more aggressive goals (<130 mm Hg), we observed target organ heterogeneity in that the risk of stroke continued to fall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal and retinal) events, and the risk of serious adverse events even increased.

β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease.

CONTEXT β-Blockers remain the standard of care after a myocardial infarction (MI). However, the benefit of β-blocker use in patients with coronary artery disease (CAD) but no history of MI, those with a remote history of MI, and those with only risk factors for CAD is unclear. OBJECTIVE To assess the association of β-blocker use with cardiovascular events in stable patients with a prior history of MI, in those with CAD but no history of MI, and in those with only risk factors for CAD. DESIGN, SETTING, AND PATIENTS Longitudinal, observational study of patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry who were divided into 3 cohorts: known prior MI (n = 14,043), known CAD without MI (n = 12,012), or those with CAD risk factors only (n = 18,653). Propensity score matching was used for the primary analyses. The last follow-up data collection was April 2009. MAIN OUTCOME MEASURES The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure. RESULTS Among the 44,708 patients, 21,860 were included in the propensity score-matched analysis. With a median follow-up of 44 months (interquartile range, 35-45 months), event rates were not significantly different in patients with β-blocker use compared with those without β-blocker use for any of the outcomes tested, even in the prior MI cohort (489 [16.93%] vs 532 [18.60%], respectively; hazard ratio [HR], 0.90 [95% CI, 0.79-1.03]; P = .14). In the CAD without MI cohort, the associated event rates were not significantly different in those with β-blocker use for the primary outcome (391 [12.94%]) vs without β-blocker use (405 [13.55%]) (HR, 0.92 [95% CI, 0.79-1.08]; P = .31), with higher rates for the secondary outcome (1101 [30.59%] vs 1002 [27.84%]; odds ratio [OR], 1.14 [95% CI, 1.03-1.27]; P = .01) and for the tertiary outcome of hospitalization (870 [24.17%] vs 773 [21.48%]; OR, 1.17 [95% CI, 1.04-1.30]; P = .01). In the cohort with CAD risk factors only, the event rates were higher for the primary outcome with β-blocker use (467 [14.22%]) vs without β-blocker use (403 [12.11%]) (HR, 1.18 [95% CI, 1.02-1.36]; P = .02), for the secondary outcome (870 [22.01%] vs 797 [20.17%]; OR, 1.12 [95% CI, 1.00-1.24]; P = .04) but not for the tertiary outcomes of MI (89 [2.82%] vs 68 [2.00%]; HR, 1.36 [95% CI, 0.97-1.90]; P = .08) and stroke (210 [6.55%] vs 168 [5.12%]; HR, 1.22 [95% CI, 0.99-1.52]; P = .06). However, in those with recent MI (≤1 year), β-blocker use was associated with a lower incidence of the secondary outcome (OR, 0.77 [95% CI, 0.64-0.92]). CONCLUSION In this observational study of patients with either CAD risk factors only, known prior MI, or known CAD without MI, the use of β-blockers was not associated with a lower risk of composite cardiovascular events.

J-curve revisited: an analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial

AIM In patients with coronary artery disease (CAD), a J-curve relationship has been reported between blood pressure (BP) and future cardiovascular events. However, this is controversial. The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD. METHODS AND RESULTS We evaluated 10 001 patients with CAD and a low-density lipoprotein (LDL) cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent BPs [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were categorized into 10 mmHg increments. The primary outcome was a composite of death from coronary disease, non-fatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal or non-fatal stroke. Among the 10 001 patients, 982 (9.82%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range, both unadjusted and adjusted (for baseline covariates, treatment effect, and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest. A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality, cardiovascular mortality, non-fatal MI, or angina. However, for the outcome of stroke, lower was better for SBP. CONCLUSION In patients with CAD, a low BP (<110-120/<60-70 mmHg) portends an increased risk of future cardiovascular events (except stroke).

Carotid Intima-Media Thickness and Antihypertensive Treatment A Meta-Analysis of Randomized Controlled Trials

Background and Purpose— Hypertension promotes carotid intima-media thickening. We reviewed the randomized controlled trials that evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intima-media thickness. Methods— We searched the PubMed and the Web of Science databases for randomized clinical trials, published in English before 2005, and included 22 trials. Results— In 8 trials including 3329 patients with diabetes or coronary heart disease, antihypertensive treatment initiated with an angiotensin-converting enzyme (ACE) inhibitor, a &bgr;-blocker, or a calcium-channel blocker (CCB), compared with placebo or no-treatment, reduced the rate of intima-media thickening by 7 &mgr;m/year (P=0.01). In 9 trials including 4564 hypertensive patients, CCBs, ACE inhibitors, an angiotensin II receptor blocker or an &agr;-blocker, compared with diuretics or &bgr;-blockers, in the presence of similar blood pressure reductions, decreased intima-media thickening by 3 &mgr;m/year (P=0.03). The overall beneficial effect of the newer over older drugs was largely attributable to the decrease of intima-media thickening by 5 &mgr;m/year (P=0.007) in 4 trials of CCBs involving 3619 patients. In 5 trials including 287 patients with hypertension or diabetes, CCBs compared with ACE inhibitors did not differentially affect blood pressure, but attenuated intima-media thickening by 23 &mgr;m/year (P=0.02). The treatment induced changes in carotid intima-media thickness correlated with the changes in lumen diameter (P=0.02), but not with the differences in achieved blood pressure (P>0.53). Conclusions— CCBs reduce carotid intima-media thickening. This mechanism might contribute to their superior protection against stroke.