Nonadherence to drug therapy is a major problem in the treatment of patients with apparent treatment-resistant hypertension (TRH). Therapeutic drug monitoring (TDM) is a useful tool for detecting and reducing nonadherence leading to effective blood pressure (BP) control. In this issue of Journal of Hypertension, Chung et al. have assessed cost-effectiveness of TDM by using a Markov model to evaluate life-years, quality-adjusted life-years (QALYs), costs and incremental cost-effectiveness ratios in TRH patients receiving either TDM-optimized therapy or standard best medical therapy. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. Cost analyses were performed from a payer's perspective. In the age group of 60-year-olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of €3854 and €3922, respectively. Given a willingness-to-pay threshold of €35 000 per QALY gained, the probability of TDM being cost-effective was at least 95% in all age groups from 30 to 90 years. Results were influenced mostly by the frequency of TDM testing, the rate of nonresponders to TDM and the magnitude of effect of TDM on BP. Thus, Chung et al. found that TDM presents a cost-effective healthcare intervention in patients diagnosed with TRH and this finding is valid for a wide range of patients, independent of sex and age.
It has been known for decades that poor drug adherence is a major problem among patients with apparent TRH [2,3] and it was pointed out as the number one problem in an algorithm for the management of apparent TRH . Before hypertension can be considered resistant to a rational triple-drug regimen in maximal doses, the physician should rule out poor adherence to the treatment regimen (including dietary and other nonpharmacological advice), adverse drug interactions, pseudotolerance (due to fluid retention), office hypertension, pseudohypertension and an unrecognized secondary cause (e.g. renovascular disease, primary aldosteronism and pheochromocytoma) . When these conditions have been excluded, haemodynamic measurements are indicated to identify the mechanism (s) at fault so that the therapeutic regimen can be modified appropriately .
Along the same lines, Ray W. Gifford Jr., already in October 1987 in printed material adopted from the upcoming Joint National Committee-4 Report , summarized the following 16 ground rules in the clinical assessment of patients with apparent TRH in order to promote adherence to treatment: inform patients of their BP level; agree on a goal BP; be sure patients understand that BP can be controlled but not cured, they cannot tell BP level by the way they feel and they should not stop treatment without discussing it with their physician; incorporate treatment into patients’ daily lifestyles; involve patients’ families in the treatment process; encourage self-monitoring of BP in selected cases; provide positive reinforcement; simplify regimen; provide simple oral and written instructions on drug dosages, side effects, therapeutic goals; encourage discussion of antihypertensive medications, side effects, problems and concerns; consider clinical-patient contracts; modify dosages and change drugs to avoid side effects; minimize cost of therapy; schedule frequent counselling visits for no-adherent patients; contact patients who miss appointments; and collaborate with other healthcare providers.
Thus, drug adherence in apparent TRH is a serious issue that has drawn the attention of experienced clinicians for many years. Recently, in a study of 84 patients taking on average five antihypertensive drugs, it was shown by measurements that no drug was detectable in the blood in 34.5% of the patients, and 65.5% of the patients fulfilled the criteria of nonadherence . Other investigators have provided similar results [6–8]. Apart from the practical and clinical challenge of convincing people with severe hypertension to take their antihypertensive medication in order to control their high blood pressure and improve their prognosis, changing patterns in drug adherence with time may introduce untoward interference with other seemingly unrelated clinical investigations involving these people with poor drug adherence. People may change their behaviour when given special attention in research, a phenomenon known as the Hawthorne effect. This may introduce a major source of bias, as patients with assumed TRH but with poor drug adherence may start taking their drugs when exposed to an additional intervention. We postulate that much of a recent controversy with a device intervention can be explained in this way [9,10].
Clinical assessment of nonadherence in routine practice is challenging . Drug adherence is usually investigated by written patient's diary or somewhat more sophisticated by electronic pill boxes, or blood and urine measurements of prescribed drugs. Measurements of drugs if feasible can provide interesting information [5–8], but it is not often used in practical clinical work especially in primary care, and the cost has been prohibitive until recently. Neither patient's diary nor electronic pill boxes are reliable to ensure drug intake. The only methods that 100% ensures true drug intake is that it is witnessed, an approach that may yield quite interesting results in patients with TRH [12,13]. However, although witnessed intake of drugs may identify adherent patients for immediate inclusion into a study, this method is not particularly practical in the long-run for the follow-up in clinical practice or research.
TDM may however be a useful tool for evaluation and improvement of adherence to drug therapy . In general, TDM allows an objective surveillance of patient adherence by repeatedly measuring concentrations of antihypertensive drugs in blood and urine. Moreover, when nonadherent patients are confronted with their low or undetectable drug levels and were provided additional counselling to overcome barriers to adherence, blood pressure control improved considerably without intensification of therapy . Although several studies [5–8] focused on the objective exclusion or confirmation of nonadherence, this recent study  utilized the information gained from TDM measurements for therapeutic purposes. The TDM results were discussed with the nonadherent patients to explore barriers to adherence and counselling was provided to overcome the specific barrier. During follow-up, SBP was reduced by 46 ± 10 mmHg in nonadherent compared with 12 ± 17 mmHg in adherent patients without intensification of the antihypertensive therapy .
The study by Chung et al. finds this method cost-effective on an exceptionally solid ground. It is of particular interest that the Markov model is based on German data and life statistics. An essential element is that TDM identifies and resolves the key to the problem, which means that patients start to take their prescribed drugs, a point that is easy to understand and of utmost clinical importance. Thus, TDM and the cost-effectiveness hereof stands for itself and should not be compared with similar analyses of controversial device intervention [9,10] in apparent TRH patients. Such analyses [15,16] may be subjected to the inherent Hawthorne as well as placebo effects, and the statistical phenomenon, regression to the mean cannot be ruled out.
Conflicts of interest
S.E.K. has received lecture and consulting honoraria from AZ, Bayer, Medtronic, Merck, Novartis, Serodus and Takeda, royalty from Gyldendal and unrestricted research grants from AZ, HemoSaphiens and Pronova. I.O. reports no conflict of interest.
1. Chung O, Vongpatanasin W, Bonaventura K, Lotan Y, Sohns C, Haverkamp W, et al. Potential cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension. J Hypertens
2. Gifford RW. An algorithm for the management of resistant hypertension. Hypertension
3. Klein LE. Compliance and blood pressure control. Hypertension
4. The 1988 report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med
5. Ceral J, Habrdova V, Vorisek V, Bima M, Pelouch R, Solar M. Difficult-to-control arterial hypertension or uncooperative patients? The assessment of serum antihypertensive drug levels to differentiate nonresponsiveness from nonadherence to recommended therapy. Hypertens Res
6. Jung O, Gechter JL, Wunder C, Paulke A, Bartel C, Geiger H, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens
7. Strauch B, Petrák O, Zelinka T, Rosa J, Somlóová Z, Indra T, et al. Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis. J Hypertens
8. Tomaszewski M, White C, Patel P, Masca N, Damani R, Hepworth J, et al. High rates of nonadherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart
9. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet
10. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med
11. Burnier M, Santschi V, Favrat B, Brunner HR. Monitoring compliance in resistant hypertension: an important step in patient management. J Hypertens Suppl
12. Fadl Elmula FEM, Hoffmann P, Fossum E, Brekke M, Gjønnæss E, Hjørnholm U, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure. Hypertension
13. Fadl Elmula FEM, Hoffman P, Larstorp AC, Fossum E, Brekke M, Kjeldsen SE, et al. Adjusted drug treatment is superior to sympathetic renal denervation in patients with true treatment resistant hypertension. Hypertension
14. Brinker S, Pandey A, Ayers C, Price A, Raheja P, Arbique D, et al. Therapeutic drug monitoring facilitates blood pressure control in resistant hypertension. J Am Coll Cardiol
15. Geisler BP, Egan BM, Cohen JT, Garner AM, Akehurst RL, Esler MD, et al. Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol
16. Dorenkamp M, Bonaventura K, Leber AW, Boldt J, Sohns C, Boldt LH, et al. Potential lifetime cost-effectiveness of catheter-based renal sympathetic denervation in patients with resistant hypertension. Eur Heart J