STUDY OF INITIAL ANTIHYPERTENSIVE THERAPY SUGGESTS THAT ACE INHIBITORS MAY BE BETTER THAN DIURETICS
Results from the recently published Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), found that initial therapy with a thiazide‐type diuretic was unsurpassed as first‐line therapy for hypertension compared with either an angiotensin‐converting‐enzyme (ACE) inhibitor or a calcium channel blocker (CCB). Now, findings from an Australian study yielded a slightly different conclusion.
The Second Australian National Blood Pressure Study (ANBP2) was a government‐supported trial conducted using a prospective, randomized, open‐label, blinded assessment of end points (PROBE) design. It involved 6083 hypertensive subjects, aged 65–84 years (mean age, 72), with a mean blood pressure of 168/91 mm Hg. Conducted at 1594 family medical practices in Australia, randomization began in April 1995 and was completed over a 3‐year period. Approximately two thirds of the participants were previously treated and had their antihypertensive therapy withdrawn at least 1 week before entering the study. Patients were randomized to either a diuretic (hydrochlorothiazide recommended) or an ACE inhibitor (enalapril recommended). Both the patient and the practitioner were aware of their assigned medication. Additional agents recommended to reduce blood pressure to less than 140/80 mm Hg, as tolerated, included the use of β blockers, CCBs, and α blockers. Ninety‐five percent of the patients were white and one half were men. Only 8% had underlying coronary artery disease, 5% had cerebrovascular disease, and 7% were diabetic.
The primary end point was all cardiovascular (CV) events (initial and recurrent) plus all‐cause mortality. CV events included major coronary events, stroke and transient ischemic attacks, heart failure (not otherwise defined), acute occlusion of any other major artery, and dissecting or ruptured aortic aneurysm.
Patients were followed for a median of 4.1 years. At the study's conclusion, 58% of those assigned the ACE inhibitor and 62% of those assigned the diuretic were still receiving the assigned treatment. Sixty‐five percent of the patients who remained on the ACE‐inhibitor and 67% who remained on diuretics were receiving monotherapy; approximately 25% were on two drugs and 6% were on three or more drugs. Additional agents required for blood pressure control included CCBs (23% in the ACE inhibitor group and 25% in the diuretic group), β blockers (11% in the ACE group and 14% in the diuretic group), and angiotensin receptor blockers (14% in the ACE group and 12% in the diuretic group). Mean systolic blood pressure was 1–2 mm Hg lower in the diuretic group for the first 2 years of the study with no difference in diastolic blood pressure reduction. At 5 years, blood pressure was equally reduced in the two groups (decreased by 26/12 mm Hg).
The frequency of the primary outcome was 56/1000 patient‐years in the ACE inhibitor group and 60/1000 patient‐years in the diuretic group—a reduction of 11% in the ACE inhibitor group which was of marginal significance (relative risk, 0.89; 95% confidence interval [CI], 0.79–1.00; p=0.05). The corresponding results, using first CV events (excluding recurrent events), were not different between the two groups (relative risk, 0.88; 95% CI, 0.77–1.01; p=0.06). Death from any cause or first CV event was similarly not different (relative risk, 0.89; 95% CI, 0.79–1.01; p=0.07). The ACE inhibitor group had a lower rate of myocardial infarction and nonfatal CV events. A similar number of strokes occurred in each group, despite a higher rate of fatal strokes in the ACE inhibitor group. In a post hoc secondary analysis of the data, despite similar reductions in blood pressure, men achieved a 17% favorable reduction in the primary end point while no difference was noted among women.
Thus, an ACE inhibitor‐based regimen was associated with better clinical outcomes than a diuretic‐based regimen, primarily in men in this study comparing relatively healthy older whites with hypertension and few risk factors.—Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin‐converting‐enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348:583–592.
Comment
This new report by Australian researchers is bound to fuel further controversy on how best to initially treat the more than 50 million patients with hypertension in the United States. The double‐blind ALL‐HAT study conducted by the National Heart, Lung, and Blood Institute found that the thiazide‐type diuretic chlorthalidone was unsurpassed as initial therapy when compared with the ACE inhibitor lisinopril (and the CCB amlodipine). In ALLHAT there were no outcome advantages for the ACE inhibitor regardless of gender or ethnicity; heart failure outcomes were worse. The present study found that those on a thiazide‐type diuretic had an 11% higher risk of CV events or death from any cause compared with those on an ACE inhibitor. How can the hypertension community reconcile these two studies? To be sure, they are not directly comparable. There are many differences between these studies, the two main differences being in their size and the method of blinding used to conduct the studies; this may have affected their results.
In comparing the ACE inhibitor and thiazide‐type diuretic groups in ALLHAT with the corresponding treatment groups in ANBP2, there were 24,309 subjects in ALLHAT and 6083 in ANBP2 with a mean follow‐up of 4.9 years and 4.1 years, respectively. This allows for many more person‐years of observation in ALLHAT. Although both ALLHAT and ANBP2 were well represented by women and older individuals, ALLHAT participants were at much higher risk for CV events than those in ANBP2. A total of 35% of ALLHAT subjects were African American; fewer than 5% of ANBP2 subjects were black. In ALLHAT 35% of subjects were diabetic compared with 7% in ANBP2. Accordingly, with a greater number of patients, their longer follow‐up, and their higher risk, there were more than eight times the number of CV events and ten times the number of heart failure events occurring in ALLHAT.
The double‐blind, randomized design used in ALLHAT is the highest scientific method used in clinical trials. In ANBP2, although the end points were blinded, the open design of the randomization allows the patient and the investigator to be aware of the treatment status. This can bias the reporting of events and side effects, and can influence drug tolerability. In ANBP2, we are not aware of the specific agent within the randomized class or the exact dose of the agent used; this can further bias the results of the study.
Adherence to therapy was different in the two studies. In ANBP2, a smaller proportion of participants remained on ACE inhibitor therapy (58%) and diuretic therapy (62%) than in ALLHAT (73% and 81%), respectively. This may affect the generalizability of the ANBP2 study.
The overall result of ANBP2 was of marginal significance. The study was powered to detect a 25% difference in the primary end point and only an 11% difference was found. In a post hoc secondary analysis, the beneficial effect of ACE inhibitor therapy was evident in men, but not in women. The validity of this comparison needs to be questioned, as there was no interaction for heterogeneity between the men and women, suggesting the difference seen between genders could be a result of chance.
Finally, there was a difference in the agents used in the two studies. ANBP2 used hydrochlorothiazide as the diuretic and enalapril as the ACE inhibitor, whereas ALLHAT used chlorthalidone and lisinopril. As there have been no head‐to‐head comparisons of these drugs in clinical trials it is difficult to directly compare their effects. The longer duration of action and greater potency of chlorthalidone in the 25 mg dose used in ALLHAT may have affected the results when compared with the hydrochlorothiazide used in ANBP2.
The differing and controversial outcomes of ANBP2 and ALLHAT should not necessarily generate confusion for the practitioner. ALLHAT was a much larger study using double‐blind methods conducted in the United States. It involved the types of high‐risk patients we often see in our practices. Accordingly, unless there is a high‐risk condition with a compelling indication for the use of another antihypertensive drug class, thiazide‐type diuretics should be used as initial drug therapy. Nevertheless, the differences found in these trials may be moot, as most hypertensive patients will continue to require two or more antihypertensive medications to achieve the minimum blood pressure goal of less than 140/90 mm Hg. About 40% of patients with hypertension appear to have an indication for an ACE inhibitor; thus, an ACE inhibitor/diuretic combination will often be required as initial therapy. Until the results of the collaborative analysis by the Blood Pressure Trialists' Collaboration are known, this seems to be a reasonable approach.
COMBINATION ACE INHIBITOR AND ARB THERAPY IMPROVES OUTCOME IN NON‐DIABETIC RENAL DISEASE
Previous studies in various forms of renal disease have found that combination therapy with an angiotensin‐converting‐enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) reduced proteinuria more than with either drug alone. The additional reduction in blood pressure that occurred when both drugs were used together may have been responsible for the improvement in outcome. In an effort to evaluate the additive effects of these same agents on renal function with equivalent reduction in blood pressure, investigators evaluated 263 patients (age range, 18–70) with nondiabetic renal disease (serum creatinine, 1.5–4.5 mg/dL or glomerular filtration rate, 20–70 cc/min/1.73 m2) from one outpatient nephrology department in Japan. Glomerular disease was the etiology of renal disease in two thirds of the subjects, hypertension in 18%, and polycystic disease in 4%. The etiology in 13% was unknown.
Subjects were randomized to one of three groups: ACE inhibitor (trandolapril, 3 mg/d), ARB (losartan, 100 mg/d), or both drugs at similar doses. Almost all patients in the three groups had equally controlled blood pressure (mean 130/75 mm Hg) with antihypertensive medications other than ACE inhibitors or ARBs.
In an intention‐to‐treat analysis with a median follow‐up of 2.9 years, the primary combined end point of time to doubling of serum creatinine or the development of end‐stage renal disease was lower in the combination‐therapy group (11%) than either the ACE‐inhibitor or ARB‐alone groups (23% in both) when added to other therapy. Urinary protein excretion was more effectively reduced in the combination group regardless of whether the baseline urinary protein excretion rate was <1 g/d, 1–3 g/d, or >3 g/d. Other factors associated with an improvement in renal function included being older, having poorer baseline renal function, achieving larger reductions in proteinuria, using diuretics, and the antiproteinuric response to trandolapril. The frequency of side effects with combination treatment was the same as with either agent alone.
In 263 nondiabetics with renal disease, a combination of an ACE inhibitor and ARB delayed the progression of renal disease more effectively than either agent alone.—Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin‐II receptor blocker and angiotensin‐converting‐enzyme inhibitor in nondiabetic renal disease (COOPERATE): a randomized controlled trial. Lancet. 2003;361:117–124.
Comment
Clinical evidence suggests that antagonism of the renin‐angiotensin‐aldosterone system delays the progression of diabetic and nondiabetic renal disease. While the maximum clinical doses of ACE inhibitor and ARB therapy can delay renal functional decline, patients still may, over time, go on to develop end‐stage renal disease.
In this trial, investigators from Japan combined clinically effective doses of an ACE inhibitor and ARB and found the combination delayed the progression of nondiabetic renal disease in those with moderate renal insufficiency and proteinuria more effectively than either agent alone. What is unique about this trial, as opposed to the Candesartan and Lisinopril Microalbuminuria (CALM) study, is the equivalent reduction in blood pressure occurring in all three groups with agents other than the randomized study drugs.
Although the study was performed in one clinic in Japan, the patient cohort reflected the status of nondiabetics with renal disease throughout Japan. The ACE gene polymorphisms studied in this cohort were representative of those throughout the country. While the most common type of renal disease was primary glomerulonephritis, combination therapy was also effective in the smaller group of patients who were hypertensive. No participants in the combination group were withdrawn from the trial, indicating that combination therapy was well tolerated.
While the most appropriate dose of trandolapril and losartan was not studied in this trial, their combination in the doses studied delayed the progression of nondiabetic renal disease and reduced proteinuria regardless of the baseline value. Before we recommend these two classes of agents as initial therapy, however, we should consider that to achieve the mean blood pressure of 130/75 mm Hg, most of the patients required diuretic therapy. This should be included in treatment.
MEASURING BLOOD PRESSURE ACCURATELY IS STILL A CHALLENGE
As high blood pressure (BP) affects approximately 25% of the US population, the accurate measurement of BP is essential to appropriately diagnose and treat hypertension. In a commentary by several members of the working group recently convened by the National Heart, Lung, and Blood Institute (NHLBI) and the American Heart Association (AHA), issues concerning the accuracy of BP measurement were discussed.
While the mercury sphygmomanometer remains the gold standard for indirect BP measurement, the concern that mercury is contaminating the environment has led many health care institutions to replace the mercury device with either aneroid or electronic/digital devices. This has created unanticipated problems in measurement accuracy. The aneroid manometer, which requires proper training for measurement, uses the auscultatory technique of listening for Korotkoff sounds. This tends to underestimate the systolic and overestimate the diastolic BP compared with intra‐arterial measurements. The automated electronic manometer assesses the oscillations of pressure in a cuff during gradual deflation. Using the point of maximal oscillation as the mean arterial pressure, an algorithm—specific for each device—then calculates the systolic and diastolic BP. These devices remain inaccurate in those with arrhythmias, particularly atrial fibrillation.
Indirect measurement by these nonmercury devices involves problems with accuracy. While the inherent biologic variability of BP and the white coat effect may affect measurement, suboptimal technique is often the cause of inaccurate measurement. Errors occur with inaccurate cuff size and application, cuff positioning, inadequate rest before measurement, too rapid a cuff deflation rate, digit bias, and lack of repeated measurements. Of note, a 5 mm Hg error either above or below the actual BP could inappropriately mislabel up to 48 million people. This would classify 27 million people as hypertensive and needlessly expose them to the expense and possible adverse effects of treatment while denying up to 21 million people the benefit of drug treatment that they require. Proper training and recertification of those performing the measurement of BP can minimize the variability of measurement due to human error.
While the Food and Drug Administration is responsible for the certification of BP devices, it works through the Association for the Advancement of Medical Instrumentation (AAMI), whose standards are voluntary. This allows some of the most common measuring devices used in practice to escape appropriate validation. While all devices require calibration and maintenance for proper measurement, the lack of mandated standards in hospitals and health care facilities has led to demonstrated problems in BP accuracy. As recently shown at the Mayo Clinic, aggressive programs of maintenance and calibration and reeducation of observers can overcome many of the problems associated with inaccurate determination of BP.
Until equipment monitoring and surveillance have been implemented, the option to institutions to continue the use of the mercury device should be offered. Validation guidelines for using the aneroid and automated devices should be evidence‐based rather than consensus‐based. Pediatric and a variety of adult‐sized cuffs should be properly termed and available for office and home use. Clinicians can assume that an aneroid device should yield as accurate a measurement as a mercury device while an oscillometric device may not yield the same accurate results. The training of observers should be required even when automated devices are used.—Jones D, Appel L, Sheps S, et al. Measuring blood pressure accurately: new and persistent challenges. JAMA. 2003;289:1027–1030.
Comment
BP measurement remains an essential part of the office visit with up to 40% of all visits related to hypertension. Despite the fact that the AHA continues to offer guidelines for the accurate assessment of BP, these recommendations are often not followed. The present commentary accordingly remains an important read for all practitioners.
Regardless of where BP is determined, proper technique will lead to a more accurate measurement. BP may be falsely elevated if patients do not avoid caffeine and tobacco for a minimum of 30 minutes beforehand and empty their bladder. Patients should be resting quietly for at least 5 minutes with legs and back supported and feet uncrossed. An appropriately sized cuff, whose inflatable portion should surround at least 80% of the arm circumference, should be used. A small BP cuff overestimates the actual measurement while too large a cuff underestimates the actual BP value. The lower edge of the cuff should lie 2–3 cm above the antecubital fossa.
The arm should be supported and angled with the antecubital fossa and stethoscope at the level of the heart. After inflating the cuff to 30 mm Hg above where the radial or brachial pulse disappears (obliteration pressure), the cuff should be deflated at a rate of 2 mm Hg/sec. Slower deflation may falsely elevate the diastolic BP while more rapid deflation may not allow the disappearance of the Korotkoff sounds to be heard.
The systolic BP is the level at which the first two consecutive sounds are heard. This should be recorded to the nearest 2 mm Hg. Odd‐numbered readings should not be used. The diastolic BP is the level at which sounds become muffled (phase IV) and disappear (phase V). If sounds continue toward zero without totally disappearing, this should be listed as a third number.
Home BP monitors may be used if they are accurate. Brachial artery‐based devices are recommended while wrist or finger devices should not be used. To ensure accurate home measurement techniques, patients should be asked to bring their home instrument into the office for yearly calibration. Self‐measurement of BP should be checked under supervision.
LIFETIME RISK OF HEART FAILURE WILL INCREASE IN BOTH MEN AND WOMEN
The lifetime risk statistic—the probability that an individual will develop a disease during their lifetime—offers the public an easy‐to‐use estimate rather than the difficult to explain age‐specific prevalence, which conveys nothing about an individual's risk for a specific disease. For example, according to the American Cancer Society, the lifetime risk for a women developing breast cancer remains at 1 in 9. Researchers from the Framingham Heart Study recently reported that 9 out of 10 adults have a lifetime risk for the development of hypertension.
Heart failure (HF) continues to remain a major public health problem affecting over five million people in the United States. Its prevalence is predicted to increase over the next several decades. In an effort to predict the lifetime risk of developing HF, Lloyd‐Jones and colleagues from the Framingham Heart Study followed 8000 men and women for up to 25 years. A total of 582 subjects developed HF. The link between chronic HF and high blood pressure was evident in both men and women.
Investigators found that a 40‐year old man with a systolic blood pressure (SBP) <140 mm Hg had a lifetime risk of developing HF of 15%, while the same individual with an SBP >160 mm Hg had a 28% lifetime risk. A 40‐year‐old woman with an SBP <140 mm Hg had a 12% lifetime risk for HF, while a woman whose SBP is >160 mm Hg has a 29% lifetime risk.
One out of every five people 40 years of age and older will develop HF; the presence of hypertension doubles that risk. As blood pressure control improves, clinicians will have opportunities to prevent the lifetime occurrence of HF.—Lloyd‐Jones D, Larson M, Leip E, et al. Lifetime risk for developing congestive heart failure. The Framingham Heart Study. Circulation. 2002;106:3068–3072.
Comment
With over a half a million new cases per year, congestive HF remains the leading cause of hospitalization for those 65 years of age and older. Despite the fact that nearly 60% of men and 49% of women die within 5 years of their diagnosis, survival has improved. Hypertension accounts for about 60% of all cases of HF in women while myocardial infarction and underlying coronary artery disease each contribute about one third of the cases in men.
The current study suggests that the lifetime risk for developing HF is 1 in 5 for both men and women.
Achieving a 20‐mm Hg decrease in SBP, regardless of gender, can reduce this risk by 50%. As the lifetime risk for HF occurring in the absence of myocardial infarction is 1 in 9 for men and 1 in 6 for women, it is imperative that we improve the control of hypertension. Only through the effective use of lifestyle modification and pharmacologic therapy aimed at the prevention and treatment of hypertension and atherosclerotic vascular disease can the potential to have a large impact on the incidence and mortality from HF be realized.
ESSENTIAL HYPERTENSION ASSOCIATED WITH REDUCED NEPHRON NUMBER
A reduced number of nephrons have been proposed as one of the factors contributing to the development of hypertension. To test this hypothesis, German investigators compared the nephron number and volume from the kidneys of 20 consecutive white subjects (18 men, two women), aged 35–59 years, who had died in accidents. Using a three‐dimensional stereologic technique, they examined glomeruli from 10 subjects with a history of essential hypertension, left ventricular hypertrophy, or both, and 10 from subjects who were normotensive (controls). Patients with hypertension had about one half the number of glomeruli per kidney (median, 702,379) compared with matched normotensive controls (median, 1,429,200). In addition, the glomerular volume in those with hypertension was increased, suggestive of hyperfiltration. Those with hypertension had no evidence of obsolescent glomeruli, which would have implied ongoing nephron loss.
Patients with hypertension have fewer glomeruli than normotensive individuals. The study suggests that persons with hypertension likely have a small number of nephrons at birth and this contributes to the increased likelihood of developing hypertension during their life‐time.—Keller G, Zimmer G, Mall G, et al. Nephron number in patients with primary hypertension. N Engl J Med. 2003;348:101–108.
Comment
The exact pathogenesis of essential hypertension remains unknown. While a number of acquired nongenetic factors have been associated with an increased likelihood for the development of hypertension, intrauterine and genetic developmental abnormalities may occur in the kidney that predispose an individual toward being hypertensive.
This study from consecutive subjects who died in traumatic accidents suggests that individuals with hypertension had fewer nephrons per kidney than those subjects who were normotensive. As there was no evidence of obsolescent glomeruli in those with hypertensive kidneys, the fewer number of nephrons must have been present at birth.
Glomerular nephrogenesis is complete several weeks before a term baby is born. This study suggests that genetic factors and/or exposure to toxic substances in utero may predispose an individual toward developing a reduced nephron number and the development of hypertension later in life. An editorial in the same journal suggests that improved perinatal nutrition may improve nephron number and reduce the chances of offspring developing hypertension later in life.