Archief Roodbont

Human Studies

Antihypertensive Drugs in People Over 80 Years of Age

It is unclear whether we should treat hypertensive people above the age of 80 years with antihypertensive drugs. This hypertensive subgroup on the one hand is liable to adverse events of drug treatment and may die of many diseases unrelated to hypertension, but on the other hand the absolute cardiovascular risk increases dramatically with higher blood pressure. The HYVET study^[1] randomized people above the age of 80 and with sustained systolic blood pressure >160 mmHg to placebo or to indapamid, 1.5 mg/day, to which perindopril, 2-4 mg/day, could be added if the target blood pressure of 150/80 was not reached. In other words, the investigators did not examine initial stages of hypertension, let alone high-normal blood pressure, and did not target so-called normal blood pressure <140/90>

Combining ACE Inhibitors and Angiotensin Receptor Blockers Does Not Help

Inhibition of the renin-angiotensin system by ACE inhibitors and by angiotensin receptor blockers is beneficial in people with hypertension, with vascular disease, in heart failure and in proteinuric nephropathies. The combination of both drugs inhibits the renin system more effectively with some further benefits in people with heart failure and in reducing proteinuria to a greater extent than monotherapy with either drug. Adverse events of the combination in heart failure are worrisome as we have detailed in this comment a year ago. The ONTARGET study enrolled 25 600 people with vascular disease, and compared ramipril 10 mg/day with the combination of telmisartan 80 mg/day plus ramipril 10 mg/day and with telmisartan 80 mg/day over 5 years.^[2] Although combination therapy had a greater effect on blood pressure (differential 2.4/ 1.4 mmHg to ramipril), it had no benefits on major cardiovascular outcomes. Renal outcomes were more frequent with combination therapy, including the often used combined endpoint of dialysis plus doubling of serum creatinine, while proteinuria was less with combination therapy.^[3] No doubt that we should not use the combination to treat hypertension or to prevent major cardiovascular or renal outcomes in people with vascular disease in general, but how about renal subgroups? ONTARGET included 3000 people with microalbuminuria, almost 1000 individuals with macroalbuminuria including 300 people with macroalbuminuria >1 g/g creatinine. We could not detect in any of those proteinuria-based subgroups a signal of renal benefit. Subgroup analyses are fraught with statistical problems and there are issues of power when going to sub-subgroups such as macroalbuminuria >1 g/g. Until further long-term studies dedicated to major renal outcomes are available, we should base our judgements on the ONTARGET trial. The use of combination therapy to lower proteinuria should be restricted to people with albuminuria in excess of 1 g/g and should be discontinued when there is no antiproteinuric effect or when eGFR decreases substantially. In the end, ONTARGET questions the use of proteinuria as a surrogate marker and suggests that we need hard renal outcomes to accept interventions and medications for our patients. The COOPERATE study is no good argument here because that study should no longer be cited until extremely serious concerns about its conduct and analysis have been dealt with.^[4,5]

Should We Screen Asymptomatic People for Carotid Artery Stenosis?

It has been argued that people with hypertension should be screened with carotid duplex ultrasound for an increase in intima-media thickness and for carotid artery stenosis even in the absence of cerebrovascular symptoms. The last guidelines of the European Society of Hypertension also favour such screening. The US Preventive Services Task Force, funded by but independent from the US government, has now issued recommendations not to screen in asymptomatic people. The USPSTF performed a systematic review of the evidence for benefit and harm of the screening.^[6] The review is revealing; duplex ultrasound is a reliable technique with a sensitivity and specificity ~90% to detect stenoses of >60-70%. However, only a minority of disabling strokes is due to carotid artery stenosis. In centres of vascular surgery with a low complication rate, high-risk people with high-grade carotid stenosis will have a 5% absolute risk reduction over 5 years for stroke and death combined. This risk reduction must be weighted against the harms of screening, namely the risks of angiography when stenosis is suspected on ultrasound and the complications of unnecessary surgery in people with false-positive screening results. It is also noted that a 60-99% stenosis of the carotid artery in asymptomatic people above age 65 may be found in 1% of the population. No single risk factor or predictive rule is known to reliably predict clinically important carotid artery stenosis. It is, however, clear that the prevalence of such stenosis increases with hypertension, male gender, smoking and known heart disease. Based on these considerations and in the absence of a study comparing stroke as an outcome and screening or no screening as interventions, USPSTF does not recommend screening for carotid artery stenosis in asymptomatic people.

Obesity Is Not a Lack of Discipline

Obesity may be a major cause of hypertension as indicated by epidemiological and interventional studies. Many physicians assume that losing weight is only a matter of discipline. We may be wrong. Everyone interested in the subject should read a controversy^[7] that reviews all aspects of that matter. There is impressive evidence that body weight is strongly genetically determined. Body weight in identical twins is closely correlated if they are raised in different families; their body weight is not related to their family if it is not the genetic family. The correlation of body weight is weaker in non-identical twins. Apart from rare monogenetic disorders like Leptin deficiency or Leptin receptor deficiency, obesity is a multigenetic disorder. In addition, epigenetic effects, like body weight and fat intake of the mother during pregnancy, play a role. The question then comes up, why does overweight (BMI 25-30/m²) and obesity (BMI >30/m²) increase in recent years, affecting now far more than 50% of adults? The hypothesis is that obesity genes are susceptibility genes, i.e. genes that cause a disease only in a 'toxic' environment. With the abundant availability of fat food and the sedentary lifestyle, such genes break their way. Such gene-environment interactions can be shown in animal models of genetic obesity and in humans. These interactions also explain why abundance of fat food has little influence on the proportion of lean people, who are genetically immune against weight gain, but has a major influence on the massive increase of morbid obesity in recent decades. Given the strong genetic background, it comes as no surprise that the long-term efficacy of weight control programmes is fraught with failure. The majority of interventional weight control studies ended before 1 year; the mean weight loss was 2-5 kg and could be maintained by a minority only. Similarly, attempts to increase physical activity, which may explain about half of the overweight problem, are usually not maintained whenever a specific programme ends. Small changes in weight admittedly result in a significant decrease in blood pressure that matches antihypertensive drug monotherapy. Whether these changes of blood pressure are maintained for more than 1-2 years is unknown. Maybe research of the few patients that successfully maintain a substantial weight loss (everyone of us knows a handful of those) may teach us more. The sad conclusion is that obesity as a genetically determined disease in modern environment has no cure. What to do in our hypertension clinics? We should inform patients about the effects of diet and exercise on blood pressure with prudent guidance of what they can expect. The strong genetic background should be made clear, and failure of a weight reduction programme, which is the rule, should not be blamed on the patient. In morbid obesity, bariatric surgery is effective over many years and has recently been associated with a reduction in cardiovascular outcomes and death with minor effects on blood pressure.

Subtle Kidney Damage First, Hypertension Later?

The kidneys play a major role in regulating blood pressure, and severe diseases of the kidney are commonly accompanied by hypertension. Whether the kidneys play a role in the genesis of primary hypertension is less clear, but there is evidence that people with primary hypertension have a lower number of glomeruli per kidney. The MESA (Multi Ethnic Study of Atherosclerosis) recruited between 2000 and 2002 adults aged 45-84 in the community to study subclinical cardiovascular disease in 6814 participants.^[8] Of these, 2767 did not have hypertension or kidney or cardiovascular disease; microalbuminuria and estimated GFR <60>2 were absent in particular. Over 3 years, 20% developed primary hypertension. Of all parameters, a higher baseline cystatin C serum level was associated with the new development of hypertension; a 15 nmol/l higher cystatin C indicated a 15% increase in risk for the development of hypertension. This relationship was absent for serum creatinine or eGFR calculated on the basis of serum creatinine. If anything, participants with a serum creatinine level of 0.8-1.5 mg/dl had a lower incidence of hypertension than those with a serum creatinine <0.8>[8a] The MESA study provides solid evidence that indeed subtle kidney damage contributes substantially to elevated blood pressure, hence to primary hypertension. Still that does not say that any hypertension is a kidney disease and we do not know why in the first place kidney function was reduced in MESA participants developing hypertension and why blood pressure increased subsequently. Further understanding of the pathophysiology may lead to new treatments or, better, prevention of hypertension.

How to Use ACE Inhibitors and Angiotensin Receptor Blockers with Renal Artery Stenosis?

Many textbooks and package inserts list renal artery stenosis indiscriminately as contraindication for the use of ACE inhibitors or angiotensin receptor blockers (collectively called 'angiotensin inhibition' in this paragraph). There are data, however, suggesting that people with renal artery stenosis may specifically benefit from both types of drugs given the fact that (a) they are more effective in lowering blood pressure in renovascular hypertension than other antihypertensives and (b) they lower cardiovascular risk in people with atherosclerotic vascular disease. The latter condition is highly prevalent in people with renal artery stenosis. Hackam et al.^[9] note that trial registries show that there are no randomized trials underway testing angiotensin inhibition in renal artery stenosis. The authors, therefore, performed a longitudinal population-based cohort study to evaluate the impact of angiotensin inhibition on renal and cardiovascular outcomes in all people 65 years of age or older in the province of Ontario, Canada. These people are entitled to free, i.e. tax-financed, health care including drug coverage. Data on hospital admissions, discharge diagnoses and interventions, on drug use, on all physician claims and on vital statistics of these Ontario residents are in central registers and were used for the present manuscript. Between 1995 and 2005, 3570 people were detected with a diagnosis of renal artery stenosis, excluding those that concomitantly were on dialysis. Total years of follow-up were 6959, so the mean follow-up time was 2 years. Angiotensin inhibition was defined as a filled prescription of one of these drugs after 3 months of the initial diagnosis of renal artery stenosis (n = 1877). The two groups, treated and not treated with angiotensin inhibition, were remarkably similar in baseline characteristics; if anything, baseline risk was somewhat higher in those treated with angiotensin inhibition. The annual incidence of a primary event (818 events), defined as death, myocardial infarction or stroke, was high, namely 11.8%, but significantly less in those treated with angiotensin inhibition (25% by unadjusted, 30% by adjusted analyses). The absolute benefit was 3 per 100 patient-years for the primary outcome. The population experienced more cardiovascular than renal events, and the single most frequent event was hospitalization for heart failure, occurring in 8%. Treatment with angiotensin inhibition also significantly reduced mortality by 44% (666 deaths) and chronic dialysis (146 cases) by 38%, but increased the risk of hospital admission for acute renal failure; 36 of those episodes were reversible, 24 unfortunately were not. The authors indicate that they cannot offer any data on follow-up serum creatinine or on severity of renal artery stenosis and its lateralization (uni- or bilateral?). Results were independent of intensity of diagnostic or interventional procedures and of number of visits with family doctors or specialists. The authors caution that other antihypertensive agents should be used first in people with renal artery stenosis and if angiotensin inhibitors are used, renal function should be very frequently controlled. I would come to slightly different conclusions because of the striking benefits of angiotensin inhibition in this study and recommend using angiotensin inhibition in most cases of unilateral renal artery stenosis and to strongly consider its use in bilateral renal artery stenosis if blood pressure is not normalized (which is rather the rule). No doubt that we need careful control of kidney function, especially early after initiation of therapy but also later on because renal artery stenoses tend to become tighter with time.