Antihypertensive drug treatment: the real‐life challenge

“One needs only to look back at the past 50 years to be amazed and deeply concerned at the worldwide enthusiasm generated by many proposed therapies for hypertension which eventually met their deserved doom–oblivion…”Goldring and Chasis, Physicians, 1965 This comment, made more than 50 years ago,1 highlights the challenges that physicians have encountered in the management of hypertension, until the late 1950s when thiazide diuretics were first introduced as a promising option for the treatment of hypertension.2 Since then, a variety of drugs have emerged and are included in the antihypertensive drug armamentarium. Current international guidelines propose several drug classes as the first treatment option for the patient with hypertension, and an abundance of studies have examined their efficacy in the reduction of blood pressure (BP) and, more importantly, in cardiovascular events.3-7 Today, physicians are challenged to provide the optimal individualized treatment option from the vast number of available antihypertensive drug classes. In the current issue of the Journal of Clinical Hypertension, Wallentin and colleagues8 analyzed data of antihypertensive drugs use from a registry of more than 2 million patients. The authors noted a 14% prevalence rate of hypertension among all study patients, with an increasing prevalence with age. Approximately half of the hypertensive population had overt cardiovascular disease; diabetes mellitus was the commonest cardiovascular comorbidity among both men and women with hypertension. Furthermore, it comes with no surprise that the type of comorbidity was associated with the type of drug class used. β-Blockers were more common among patients with atrial fibrillation, coronary artery disease, and heart failure, and angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers were the most frequently administrated drugs in the hypertensive population with diabetes mellitus and heart failure, whereas mineralocorticoid antagonists and diuretics were more frequently used in patients with heart failure.8 The 14% prevalence rate of hypertension among the study patients is lower than anticipated. In an analysis of global data from population-based cross-sectional surveys, the prevalence rate of hypertension was approximately 26%.9 Similarly, in a more recent study in more than 19 million patients, the global age-standardized prevalence of raised BP was 24.1% in men and 20.1% in women.10 Several other large registries reported the prevalence of hypertension in various study populations. Among 15 152 patients with myocardial infarction and 14 820 controls in the INTERHEART study,11 the prevalence rate of hypertension was approximately 20% in the controls and 39% in patients with myocardial infarction. Given the nature of the study and the selection of patients based on the presence or absence of myocardial infarction, the data of this registry might be questionable in terms of the true prevalence of hypertension. In the EPIC (European Prospective Investigation into Cancer and Nutrition) study,12 the prevalence of elevated BP (>140/90 mm Hg) was found in 44.0% and 33.9% of men and women, respectively. This is in agreement with data from the previously mentioned global estimate of hypertension prevalence, where the prevalence rate of hypertension in European countries ranged from 28.4% to 55.3%.9 Additional data come from the National Health and Nutrition Examination Survey (NHANES) where the prevalence rate of hypertension in US adults aged 18 years and older was 29.1%, and similar prevalence rates were noted among men (29.7%) and women (28.5%).13 Wallentin and colleagues8 report that half of the patients with hypertension remain undiagnosed. This assumption is in agreement with data from the aforementioned large registry, where the prevalence rate of hypertension in Sweden was double (28%) that reported in the study.10 In the NHANES report,13 approximately 81% of the patients with hypertension were aware of their hypertensive status. Of note, men seem to be less aware of their BP levels compared with women (80.2% vs 85.4% for men and women, respectively). In contrast, it was shown that the awareness of increased BP status ranges from 33% to 58% in Sweden,14 which is in agreement with the statement of Wallentin and colleagues. Since approximately 7.6 million deaths are attributed to high BP annually,15 the 14% prevalence rate in the present study raises several concerns for the level of awareness in the Sweden population and the potential morbidity and mortality complications. In addition, the study highlights important differences in terms of antihypertensive treatment choice based on sex and age. While calcium channel blockers (CCBs) and ACEIs were more commonly administrated in men, angiotensin receptor blockers and diuretics were more frequently used in women. Data on the efficacy of different drugs classes in men compared with women do not seem to justify these findings. The Heart Attack Trial and Hypertension Care Computing Project have shown that β-blockers are more efficient in reducing mortality in men than in women.16, 17 The ANBP2 (Second Australian National Blood Pressure) study18 demonstrated similar BP reduction between the sexes with the use of either diuretics or ACEIs. Cardiovascular outcomes were similar across groups taking either drug in women. On the contrary, greater cardiovascular effects were observed in men with the use of ACEIs compared with diuretics.18 However, the most important data come from a large meta-analysis of 31 trials with 100 000 men and 90 000 women from the Blood Pressure Lowering Treatment Trialists’ Collaboration. No significant differences were noted in the BP-lowering effects of various antihypertensive drugs between men and women. More importantly, cardiovascular outcomes were also similar across the two sexes independently of the drug class used. Among various comparisons and outcomes examined, marginally significant differences between the two sexes were noted only in stroke risk, with calcium channel blockers offering greater benefits in women than in men, while all other comparisons on outcomes between the two sexes did not unveil any differences.19 In general, no firm data exist to date favoring one class over another in either sex. In contrast, important differences between men and women are noted in the frequency of adverse events with several drug classes that are in agreement with the preference of CCBs and ACEIs in men and angiotensin receptor blockers and diuretics in women. In TOMHS (Treatment of Mild Hypertension Study) and LIFE (Losartan Intervention for Endpoint Reduction in Hypertension Study), the frequency of adverse events with BP-lowering drugs was higher in women than in men.20, 21 ACEI-induced cough is more frequent in women than in men.22 Furthermore, CCB use more often causes edema in women than in men.23 Last, the preference of diuretic use in women might be partially explained by the diuretics-induced reduction in hip fractures in older women.24 The use of CCBs, diuretics, and β-blockers seems to be preferred in older than younger patients. Older data from small studies suggest that β-blockers are more effective in younger patients25 In contrast, only 20% of older patients with hypertension achieve BP goals with β-blockers.25 The increased frequency of other comorbidities in which β-blockers are recommended as a first-line treatment option (heart failure, atrial fibrillation, ischemic heart disease)3-6 and the off-label use of these drugs in conditions where β-blockage exerts favorable results (migraines, hyperthyroidism)26 might explain (at least in part) the preference of these drugs in older individuals. Moreover, β-blockers were shown to produce ameliorating effects in strokes and total mortality in the STOP-Hypertension (Swedish Trial in Old Patients With Hypertension).27 Supporting data for the use of CCBs in the elderly have emerged from the Syst-Eur (Systolic Hypertension in Europe)28 and Syst-China (Systolic Hypertension in China)29 trials in which the use of CCBs in older patients with hypertension was associated with significant BP-lowering and cardiovascular effects. In addition, the STOP-Hypertension 2 trial suggested a similar efficacy of CCBs compared with β-blockers and diuretics in the reduction of cardiovascular events in older individuals.30 Last, ACEIs were more commonly prescribed in men and women younger than 60 and 50 years, respectively. The IDEAL (Identification of the Determinants of the Efficacy of Arterial Blood Pressure Lowering Drugs) trial31 suggested that the BP-lowering effect of perindopril decreased by 2 mm Hg every 10 years of age increase in both sexes. Since renin levels are more likely to be elevated in younger and reduced in older individuals, a modified version of the renin concept has been proposed32 and adopted by the British guidelines7 to achieve better BP response to drug treatment. It is thus suggested that drugs that inhibit the renin angiotensin system are preferred in younger patients, while CCBs and diuretics are preferred in older patients with hypertension.7 Consequently, the higher frequency of ACEIs in younger groups in the study by Wallentin and colleagues could theoretically be a result of better BP response. The strength of this study lies in the large number of participants from a real-life setting. Patients were not selected but extracted from a highly valid database, thus reducing the risk of selection bias. In addition, the diagnosis of hypertension was not self-reported and was performed by the treating physician. This, however, is also a limitation of the study, since the accuracy of the diagnostic procedures cannot be evaluated and might have been affected by the measurement technique or the presence of masked or white-coat hypertension. Last, the true prevalence of hypertension in the Swedish population has not been evaluated, since a large proportion of persons with hypertension remains undiagnosed. Collectively, the study has provided important data of antihypertensive drug treatment options. Clinical studies provide important results that define the antihypertensive treatment guidelines. However, the implementation of the guidelines in real-life settings seems to be lacking and BP-lowering drugs are used in a manner that is not in total compliance with the suggested one. The differences in the frequency of adverse events in men versus women and the variant BP responses with each drug, along with the presence of other comorbidities in younger versus older patients, might explain the noted differences. Given the significant BP-related mortality and morbidity in real life, the calculated prevalence in the study creates concerns for the awareness in the Swedish population and highlights the need to increase efforts to adequately diagnose and manage the hypertensive population.