Hypertension: A Forceful Foursome?

4. April 2017

In dealing with patients with arterial hypertension, lifestyle changes are not always enough. Cardiologists now show that those affected benefit from four low-dose antihypertensive medications in combination. Their study is nevertheless not free of weaknesses.

“Hypertension has become a social problem and permeates all levels of society – not just the elderly population, as widely believed”, Professor Dr. Burkhard Weisser stated at the last congress of the German Hypertension League, giving something to bear in mind. He does research at the Institute of Sports Science at the Christian Albrecht University of Kiel (Germany). According to Weisser, currently about three percent of all children and adolescents suffer from high blood pressure. Expert associations see obesity and physical inactivity in particular as the basis for this. For physicians, lifestyle interventions are the first priority here (as they are with the elderly). Should these achieve no success, pulling out the prescription pad is the doctor’s only option.

The combination does the trick

“Most patients however are treated using monotherapy, leading to poor results”, criticises Professor Dr. Clara K. Chow of the University of Sydney. Blood pressure levels only get reduced by 05/09 mmHg. “Therefore, new strategies are urgently needed”.


Clara K. Chow. © University of Sydney

In a literature review, the cardiologist found further indicators. She evaluated 36 older studies involving 4,721 participants. It was found that a drug given already as a quarter dosage, according to the guideline, reduces blood pressure versus placebo by 2.5 mm Hg. With two active ingredients, she calculated a figure of 5.7 mm Hg. Chow then came upon an idea. She combined 37.5 mg irbesartan,1.25 mg amlodipine, 6.25 mg hydrochlorothiazide and 12.5 mg atenolol in a quad pill.

Small amount, big impact

The scientist tested out her concept in a small randomised study. She recruited 21 people with arterial hypertension. Her average participant had a blood pressure of 154/90 mm Hg as measured in her clinic. Over a long-term blood pressure measurement over 24 hours, doctors measured a blood pressure level of 140/87 mmHg.

The researcher chose a crossover design. All subjects were randomised to receive quadruple pills or placebos. After four weeks, a two-week washout period followed. Then the other alternative was administered. Under verum, blood pressure as measured in the doctor’s clinic decreased by 22/13 mm Hg. The 24-hour ECG systolic measures were 19 mm Hg lower. All differences proved to be statistically significant.

For various reasons, only 18 patients completed the study. They all reached the goal of 140/90 mm Hg through the quadruple combination. With placebo, this was achieved by only six of 18 patients. Chow says the combination is ideal for successful initial therapy. “The minimisation of side effects is important for long-term treatments – we saw no problems in this study”. She therefore has hopes for higher patient compliance. Since all the ingredients are individually approved, the expert does not expect to deal with any major hurdles.

No reason for euphoria

Nevertheless, a few critical issues remain. Professor Dr. Thomas Eschenhagen, Director of the Institute of Experimental and Clinical Pharmacology and Toxicology at the University Hospital Hamburg-Eppendorf (Germany), in a blog post evaluated atenolol to “no longer be first choice” for use in antihypertensive therapy – with the following exception: “In the instance of coronary heart disease, after myocardial infarction, with heart weaknesses, atrial fibrillation or other cardiac arrhythmias, beta blockers remain the first choice”.

The figures should be treated with caution as well. The George Institute for Global Health, in referring here – literally – to a “pilot study”, appears to be – in view of the total number of hypertension patients involved here – really taking things quite too far. In order to be able to detect potential side effects, the time involved is too short. Cardiovascular or renal endpoints are also not able to be stated for the same reason. International professional societies are demanding precisely this.

Good idea – bad data

Chow and colleagues now want a large-scale, longer-term study. In doing so, the end result may not be highly gratifying, as an inspection of the so-called “poly pills” shows.

Nicholas Wald, long-time head of the Wolfson Institute of Preventive Medicine in London, suggested giving all patients over the age of 55 a poly pill, independent of cardiovascular risk. The preparation contains three antihypertensives and a statin in half the standard dose. Added to this were 0.8 mg of folic acid and 75 mg of acetylsalicylic acid.

Wald’s hopes of reducing the rate of cardiovascular disease by 80 percent and extending life expectancy by 11 years were not realised. According to a meta-analysis involving 7,047 participants, systolic blood pressure decreased by a not insignificant 7.05 mm Hg. In exchange for this, patients paid a high price on account of various side effects. Statements regarding cardiovascular or renal endpoints were also not possible here. What’s more, with the HOPE 3 study expectations were met only partially.

The fate of Chow’s quad pill is something which still remains unknown.

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