How Many Drugs, Which Drugs -- or Is it Nondrugs -- to Treat Hypertension?

February 10, 2003

Introduction

How many drugs does it take to control hypertension? A possible answer to this question comes this month from the results of a small Australian study that compared the 4 main classes of antihypertensive drugs. The investigators found that the reason most patients need multidrug therapy to control their hypertension may be because, while some antihypertensive drugs have a consistent effect, others reach maximum effect at different times of the day or night.

Another question, always asked after a drug has shown benefit in a clinical trial, is whether the results represent a "class effect." The results of a Canadian study suggest that, at least for the class of long-acting dihydropyridine calcium channel blockers (CCBs), the drugs are not homogeneous enough to generalize positive results across the class.

At a more basic level, this month's news also includes support for the hypothesis that people with a reduced number of nephrons are more likely to have renal disease, hypertension, or both. German researchers studying patients at autopsy found a reduced number of glomeruli and a larger glomerular volume in the hypertensive patients compared with normotensive controls.

Finally, regarding an issue that the treating physician is often presented with by a hypertensive patient, ie, nondrug therapies for hypertension, a fermented milk drink marketed in Finland has been reported to lower blood pressure to the same degree as that seen with drugs in published clinical trials. On the other hand, an unapproved nonprescription medication, marketed as a Chinese traditional medicine for hypertension, was recalled in January after the Food and Drug Administration (FDA) determined that it contained ingredients that could pose a serious risk to health.

It is a well-known tenet of good medical practice that patients with hypertension will probably need a combination of drugs of different classes for effective treatment. The most recent evidence of this was seen in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), in which 63% of the patients enrolled were on 2 or more drugs by the end of the study.[1] Now a possible explanation for why multiple drug therapy is so often necessary to control hypertension has come from a small study in which different classes of drugs were shown to work most effectively at different times of the day.[2]

Researchers from the University of Melbourne, Australia, studied the antihypertensive effects of a beta-blocker, an angiotensin-converting enzyme (ACE) inhibitor, a CCB, and a diuretic in previously untreated patients aged > 65 years with systolic blood pressure (SBP) > 150 mm Hg. Twenty-four patients were randomized in a double-blind, balanced design to atenolol 25 mg, perindopril 4 mg, felodipine 5 mg, hydrochlorothiazide 20 mg, or placebo for 4 weeks. They were then force titrated to double dose, unless contraindicated, and after 1 month at the higher dose, crossed over to the next drug. In total, each patient received 5 treatment regimens over 8 weeks.

Ambulatory blood pressure monitoring (ABPM) was done over 1 hour at monthly visits (clinic SBP) and over 25-26 hours at the end of each 2-month drug treatment period (24-hour mean SBP); pressures were recorded during 3 periods of the day: morning (6:00 AM-9:00 AM), awake (9:00 AM-10:00 PM), and sleep (12:00 AM-6:00 AM). Medication was taken at 9:00 AM.

All 4 classes of drugs significantly lowered clinic SBP (P < .05) and 24-hour mean SBP (P < .05), although the reductions in SBP were greater with the felodipine and hydrochlorothiazide, confirming the results of a larger study performed by the same investigators with the same drugs.[3] However, hydrochlorothiazide and felodipine had a relatively consistent effect on blood pressure compared with the effects of atenolol and perindopril, which were highly dependent on the time of day. Atenolol was more effective during the awake hours, but had no significant effect during the sleep or morning periods. By contrast, perindopril lowered blood pressure more during sleep hours than awake hours, when it was relatively ineffective. The fall in sleep blood pressure produced by perindopril was, however, greater than with the other drugs.

Noting the importance of sleep blood pressure in determining whether end-organ damage, particularly cardiac hypertrophy, occurs, lead researcher Professor Trefor Morgan, MD, suggested that the failure of atenolol to reduce sleep blood pressure might explain why beta-blockers are relatively ineffective at reducing cardiac hypertrophy[4] and in preventing cardiac morbidity and mortality when used as monotherapy for hypertension.[5,6] He also suggested that the greater effectiveness of perindopril during the night might partly explain why ACE inhibitors are so effective in reducing cardiac hypertrophy[4] and deaths due to coronary artery disease, as demonstrated in the Heart Outcomes Prevention Evaluation (HOPE) trial.[7]

Further evidence that even drugs within the same antihypertensive subclass may act differently has come from a recent Canadian study.[8] Professor Frans H. H. Leenen, MD, PhD, and colleagues at the University of Ottawa (Ontario, Canada) evaluated the effects of 2 long-acting, once-daily CCBs, nifedipine-gastrointestinal therapeutic system (GITS) and felodipine extended release (ER), compared with enalapril, on blood pressure, sympathetic activity, and left ventricular (LV) mass. It was previously suggested that the GITS formulation of CCBs such as nifedipine and amlodipine maintain good blood pressure control over the full 24-hour dosing period, without causing dose-related increases in sympathetic activity, whereas felodipine-ER provides only intermittent blood pressure control, with an accompanying degree of sympathomimetic activation.

In the study by Professor Leenen and colleagues, patients were given 30 weeks of treatment with nifedipine-GITS 30 mg/day, felodipine-ER 5 mg/day, or enalapril 10 mg/day, all once daily. Doses were increased to 60 mg/day, 10 mg/day, or 20 mg/day, respectively, if office blood pressure remained ≥ 160/90 mm Hg at the end of the dosing interval. Nifedipine-GITS produces a consistent decrease in blood pressure, as measured by 24-hour ABPM, whereas felodipine-ER caused a more marked fall during the day. The blood pressure-lowering effect of enalapril diminished during the night and had disappeared by morning. Only felodipine increased sympathetic activity, as measured by increased supine and standing plasma noradrenaline. Nifedipine-GITS and enalapril were more effective than felodipine in reducing LV mass in blood pressure responders. The investigators concluded that, compared with felodipine-ER, nifedipine-GITS has a superior profile regarding 24-hour blood pressure control, lack of sympathetic activation, and LV mass regression.

Further evidence that the number of nephrons at birth may be a determinant of cardiovascular abnormalities during adult life has emerged from a recent study from Germany.[9] Gunhild Keller, MD (University of Heidelberg, Germany) and colleagues have found that, compared with normotensive subjects, the number of nephrons is reduced in white patients with primary hypertension. They suggest that this reduced number may be due to genetic factors, further supporting the hypothesis that a low nephron population at birth may gradually damage the kidney as a result of increased workload per nephron, thus leading to hypertension.

To test the hypothesis that a low nephron number increases the risk of essential hypertension, Dr. Keller and colleagues studied the number and volume of glomeruli from kidneys in 10 patients aged 35-59 years with a history of primary hypertension or LV hypertrophy, or both, vs the number and volume of glomeruli in 10 normotensive subjects matched for age, height, and weight. All subjects had died in accidents. A 3-dimensional stereologic technique was used to compare nephron numbers and volumes. The patients with hypertension had a median of 702,379 glomeruli per kidney, significantly fewer than the normotensive subjects who had a median of 1,439,200 glomeruli per kidney. Patients with hypertension also had a significantly greater glomerular volume than the controls (median 6.50 x 10-3 mm3 vs 2.79 x 10-3 mm3; P < .001), but few obsolescent glomeruli. The patients with hypertension also had more severe arteriolosclerosis than the controls.

In an accompanying commentary,[10] Julie R. Ingelfinger, MD (Massachusetts General Hospital, Boston), calls the data from the study "provocative, but not definitive." She notes that "the roots of hypertension are multiple, and it would be oversimplification to state that nephron number alone is the key to primary hypertension." Nonetheless, she believes that the concept of decreased nephron endowment is useful because it points to the possible preventive action of improved nutrition in pregnant women, which might reduce the frequency of hypertension in susceptible offspring in later life.

Fermented milk products have been the subject of investigation for their antihypertensive properties since ACE-inhibiting peptides were isolated from milk proteins and found to lower blood pressure in animals. Research into these bioactive peptides has been carried out mainly in Finland and Japan, where fermented milk-based drinks are marketed as helping to reduce blood pressure. Few controlled studies of fermented milk have been conducted in humans,[11,12] but investigators from Helsinki have now reported a randomized, controlled clinical trial in which they claim a fermented milk product produced a fall in blood pressure in hypertensive patients similar to that seen in randomized controlled trials of drugs.[13]

Ritta Korpela, MD, and colleagues randomized patients with hypertension (mean SBP ≥ 140 mm Hg and mean diastolic blood pressure (DBP) ≥ 90 mm Hg) to receive either Evolus (Valio, Helsinki), a Lactobacillus helveticus LBK-16H fermented milk, or a control milk product for 21 weeks. Blood pressure in the test group was lower than in the controls by a mean of 6.7 +/- 3.0 mm Hg SBP and 3.6 +/- 1.9 mm Hg DBP, a significant difference for SBP (P < .030) and a tendency toward significance for DBP (P < .059).

The test milk was confirmed as having ACE inhibitory activity in vitro, due to the presence of the peptides Ile-Pro-Pro and Val-Pro-Pro, which could explain, as least in part, the antihypertensive effect seen. The investigators do not rule out other antihypertensive mechanisms, including the higher calcium content or the presence of live starter bacteria in the test milk. Nonetheless, they believe that fermented milk is potentially useful in the dietary treatment of hypertension.

The Finns are possibly unique in their innovative approach to dietary cardiovascular therapy, with consumers able to purchase cholesterol-lowering Benecol products (Raiso) and coronary disease risk-reducing food products from the HK Ruokatalo food merchants.

A non-FDA-approved product marketed as a nondrug "health product" for the treatment of hypertension was recalled after the FDA determined that it contained ingredients that could pose potentially serious health risks to consumers.[14] Ancom Anti-Hypertensive Compound Tablets were labeled as containing prescription ingredients such as reserpine (per tablet: 30 mg), diazepam (1 mg), promethazine (2.1 mg), and hydrochlorothiazide (3.1 mg). The product was recalled by Herbsland, Inc, in cooperation with the FDA. Customers who purchased the tablets were urged to stop using them and to return the bottles to the place of purchase for a refund.

Ancom, manufactured in China by Shanghai Pharmaceutical Industry Corp, was sold in bottles of 100 tablets by distributors and retailers in the New York metropolitan area and via the Internet on a number of sites advertising Chinese or Asian medicines. As of January 31, Internet sites were still advertising Ancom tablets, citing "clinical reports of the big hospitals in Shanghai," and recommending a dosage of 1-2 tablets 3 times daily, reducing to a maintenance dose of 1 tablets 1-2 times daily.

References

  1. The ALLHAT Officers and Co-ordinators for the ALLHAT Collaborative Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:1981-1997. Abstract

  2. Morgan TO, Anderson A. Different drug classes have variable effects on blood pressure depending on the time of day. Am J Hypertens. 2003;16:46-50. Abstract

  3. Morgan TO, Anderson AIE, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of hypertension. Am J Hypertens. 2001;14:241-247. Abstract

  4. Dahlof B, Pennnert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A metaanalysis of 109 treatment studies. Am J Hypertens. 1992;18:445-451. Abstract

  5. Medical Research Council Working Party. Medical Research Council trial of treatment of mild hypertension: principal results. Br Med J. 1985;291:97-104. Abstract

  6. Medical Research Council of treatment of hypertension in older adults. Principal results. BMJ. 1992;304:405-412. Abstract

  7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: N Engl J Med. 2000;342:145-153. Abstract

  8. Leenen FHH, Myers MG, Hoyner CD, Toal CB. Differential effects of once-daily antihypertensive drugs on blood pressure, left ventricle mass and sympathetic activity: Nifedipine-GITS versus felodipine-ER versus enalapril. Can J Cardiol. 2002;18:1285-1293. Abstract

  9. Keller G, Zimmer G, Mall G, et al. Nephron number in patients with primary hypertension. N Engl J Med. 2003;348:101-108. Abstract

  10. Ingelfinger JR. Is microanatomy destiny? N Engl J Med. 2003;348:99-100. Available at: http://content.nejm.org/cgi/content/full/348/2/99.

  11. Hata Y, Yamamoto N, Ohni M, et al. A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr. 1996;64:767-771. Abstract

  12. Seppo L, Kerojoki O, Suomalainen T, Korpela R. The effect of a Lactobacillus helveticus LBK-16 H fermented mild on hypertension: a pilot study in humans. Milchwissenschaft. 2002;57:124-127.

  13. Seppo L, Jauhiainen T, Poussa T, Korpela R. A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr. 2003;77:326-330. Abstract

  14. Herbsland Company recalls Ancom Anti-Hypertensive Compound Tablets. Available at: http://www.fda.gov/oc/po/firmrecalls/herbsland01_03.html. Accessed February 5, 2003.