Spectre de l’hypertension artérielle résistante chez des africains autochtones fréquentant un centre de soins specializes: Etude transversal.

 

BASIL N OKEAHIALAM, FWACP.

 

RESUME

 

Introduction: Malgré l’existence actuelle de ce qui peut être considéré comme un arsenal thérapeutique impressionnant pour le contrôle de la pression artérielle, de nombreux hypertendus restent largement incontrôlés pour cause de non observance. Dans certains cas, le contrôle reste médiocre malgré une bonne observance, exposant ces hypertendus à des risques. Ces cas de résistance ont un phénotype extrême appelé hypertension réfractaire. Les identifier et les profiler donnerait un aperçu du problème, dans l'espoir de mieux prendre en charge leurs particularités dans notre contexte.

Méthodes: Il s'agissait d'une étude transversale, portant sur des patients fréquentant un établissement de soins spécialisés dans la prise en charge de l’hypertension artérielle depuis plus de 3 mois. Ils ont été évalués pour identifier les cas résistants au traitement et parmi ceux-ci, les réfractaires. Leurs caractéristiques épidémiologiques et leurs comorbidités ont été documentées.

 

Résultats: Un total de 437 hypertendus a été étudié, dont211 hommes et 226 femmes, âgés de 30 à 89 ans. Deux cent cinquante-quatre (254) d'entre eux étaient résistants, parmilesquels144 non contrôlés et 93 contrôlés, bien que résistants. Sur les 254, 17 (11 H, 6 F) étaient réfractaires. Les réfractaires étaient plus âgés, en surpoids et présentaient plus de comorbidités. Le stress psychosocial intense et les maladies du tissue conjonctif étaient également fréquemment retrouvés chez eux.

Conclusion: Une petite proportion d'hypertendus résistants, principalement les personnes âgées, les personnes en surpoids ou obèses et ceux présentant des troubles métaboliques, semblent être plus réfractaires au traitement et auraient besoin d'approches innovantes pour en atténuer les conséquences indésirables et améliorer les résultants de leur prise en charge. Le stress psychosocial intense et les maladies du tissue conjonctif semblent fréquents dans ce sous-groupe.

 

MOTS CLES

Hypertension, contrôlée, résistante, réfractaire, africains

 

SUMMARY

 

Introduction: Despite what is seen to be an impressive armamentarium for blood pressure control, many hypertensives remain uncontrolled largely for non-adherence. In some cases, control remains poor despite adherence, exposing such hypertensives to risk. These cases of resistance have an extreme phenotype called refractory hypertension. Identifying and profiling them will give an insight into the problem, with the hope of addressing their peculiarity for benefit.

Methods: This was a cross-sectional study of hypertensives attending a specialized hypertension primary care facility for over 3 months. They were assessed to identify those resistant to treatment and from these, those refractory. Their epidemiological characteristics and co-morbidities were documented.

Results: A total of 437 hypertensives were studied, 211 males and 226 females; aged between 30 and 89 years. 254 of these were resistant, uncontrolled in 144 while 93 were controlled, though resistant. Of the 254, 17 (11 M, 6 F) were refractory. The refractory ones were older, heavier, and had more co-morbidities. Intense psychosocial stress and connective tissue diseases were also prominent.

Conclusion: A small proportion of resistant hypertensives mostly the elderly, the overweight/obese, and the dysmetabolic are likely to be refractory to treatment and would need innovative approaches to mitigate adverse consequences and improve outcomes. Intense psychosocial stress and connective tissue disease also appeared relevant.

 

KEY WORDS

Hypertension, Control, Resistant, Refractory, Africans.

 

Cardiology Sub-Unit 1, Department of Medicine, Jos University Teaching Hospital, Jos Nigeria

Adresse pour correspondance 

Basil N OKEAHIALAM

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Phone +2348051499271

ORCID ID: 0000-0001-5351.1734

 

INTRODUCTION

 

Hypertension in the African is said to start earlier, attain greater severity, and run a more devastating course with more debilitating consequences. ¹ Health inequity, ² genetics ³ and undue stress brought about by modern living ⁴ may be at the root of these. Generally speaking, hypertension is the foremost harbinger of cardiovascular diseases being associated with a greater part of stroke, heart failure and ischemic heart disease globally; and hence responsible in large part for the gruesome morbi-mortality statistics related to cardiovascular diseases. ⁵

Resistance has been said to pose a problem of poorer outcomes in uninsured populations. ⁶ Its consequences in Africans will be expectedly grimmer. An extreme phenotype of resistant hypertension known as refractory hypertension has not been studied in sub-Saharan Africa, but in a study of resistant hypertension, Nausen et al ⁷ concluded that there is a huge dearth of literature on this subject begging to be filled. This is because by its nature, difficult to treat hypertension, which is common in sub-Saharan Africa, ⁸places patients at risk of target organ disease. ⁹

One therefore retrospectively studied hypertensives accessing care in this private specialized hypertension service to determine the profile of those resistant to treatment with an emphasis on the extreme phenotype known as refractory hypertension. This is to contribute information on this subject in a native African population. It has been said that characterizing them charts the path to defining mechanisms of resistance. ¹⁰

 

 

METHODS

 

The author runs a specialized primary care center on Internal Medicine cases; with a huge emphasis on Cardiology. The bulk of the patients are hypertensive. They come largely on self - referral or on recommendation of health care providers and relatives with knowledge about the service. Clientele cut across gender, age, ethnicity, social class, and religion. The appointment cycle is between 2 weeks and 3 months; so this study lasted for 3 months between 16^th May and 8^th August 2018. The focus was hypertension without complications like stroke, myocardial infarction, heart failure, or kidney failure. Being patients known from follow-up, secondary hypertension had been excluded and issues of adherence had been taken care of. Notwithstanding, the patients were questioned about adherence on enrolment day to ascertain status. Once seen, patients were not considered again even if they were given appointments in-between; to avoid duplication. Individual consent was sought for the study after full information; and they willingly obliged since largely it was all about anonymized information from the records. Notwithstanding, a request for a waiver to face the full panel and permission to publish data generated in the course of clinical duties was made to the Chair of Research and Ethics Committee of Jos University Teaching Hospital where the author is officially affiliated to conform with standard ethical procedures. This was granted (Ref: JUTH/DCS/ADM/127/XXXI/2248) after reviewing the process and the data generating process, thus ensuring conformity with Helsinki declaration guidelines. Information extracted were: age, gender, duration of attendance for care, the status of hypertension, drugs prescribed for hypertension, any other drug(s) prescribed, weight, and co-morbidities.

Resistant hypertension has been defined as blood pressure that remained above goal >140/90 mmHg despite being adherent to greater or equal to 3 anti-hypertensives from different classes; one of which is a diuretic, unless contraindicated due to prior adverse effect or intolerance. ¹⁰ If blood pressure is only controlled with 4 or more medications, it is defined as controlled resistant hypertension. ¹¹To qualify for enrolment, apart from being hypertensive with none of the complications listed above, they had to have attended care for a minimum of 6 months with blood pressure values on the last 3 visits available. These have been established as pre-conditions before the diagnosis of refractory hypertension can be made. ¹⁰ No one who had attended for a minimum of 6 had any of the last 3 visits blood pressure records missing. If in 2 out of 3 previous visits, the blood pressure was above goal; such a patient was branded resistant if on 3 or more anti-hypertensives one of which was a diuretic.

On the day of enrolment, only the author with an Accosson brand mercury sphygmomanometer with appropriate size cuff took blood pressure after at least 5 minutes of rest in standard fashion. They were also asked about a history of ongoing life stressful event, hyper-alerting response in clinic encounters and persisting insomnia. If on that day of enrolment blood pressure was good, the patient was considered as controlled resistant; but if blood pressure was above goal on that day, the patient was considered as uncontrolled resistant. If the uncontrolled resistant hypertensive was on 5 or more drugs one of which was Spironolactone, such a patient was considered to have refractory hypertension. ¹²

Descriptive statistics were applied on generated data and rendered as numbers and proportions in percentages.

 

RESULTS

A total of 437hypertensives satisfied the inclusion criteria; 211 of whom were males and 226 females. They had attended care for between 6 and 288 months, and aged from 30 to 89 years. A total of 254 out of the 437 (58.1%) qualified as apparently resistant. Fourteen out of these 254 apparent- resistant (5.5%) cases on enrolment were non-adherent and would pass for pseudo-resistance.  Five of them were adherent all the while but skipped doses on clinic appointment days; the reasons being to allow the doctor to know the status without medication or avoiding the need for frequent micturition. In the other 9, they ran out of their stock for between 2 and 14 days and decided to wait till review just in case the regimen would be revised. Considering this, notwithstanding that no ambulatory blood pressure monitoring was done 240 out of 437 (54.9%) would now qualify as resistant hypertension. One hundred and forty-four out of the 240 resistant hypertensives (60%) were controlled on the day of enrolment and branded “controlled resistant”. They were all adherent. There were more females than males; 74 versus 70. Ninety-six out of the 240 (40%) qualifying as resistant had blood pressures above goal on the day of enrolment and branded “uncontrolled resistant” There were more males (49) than females (47) in this category. Seventeen, (11 males and 6 females) out of the 240 resistant hypertensives (7.1%) remained above goal despite the use of 5 or more drugs and were branded as “refractory”. Looked at in the background of the whole 437 in the cohort they came to 3.9%, but in the background of the 96 with uncontrolled resistant hypertension, it was 17.7%.

A closer look at the extreme phenotype of resistant hypertension, the refractory sub-class showed that their ages spanned from 35 to 73 years with clustering between the 5^th and 7^th decades. They were mostly heavy with 8 out of the 17 weighing over 100 kilograms; actually from 104 to 140 kilograms. Twelve of the 17 had co-morbidities: 5 with metabolic syndrome, 3 with only diabetes mellitus, 2 under intense psychological stress; and in two women there was a diagnosis of connective tissue disease. In another 5 there was no obvious association. Table 1 shows the profile of this phenotype.

 

 

DISCUSSION

 

Hypertension is underpinned by a complex trait regulated by multiple physiological pathways. ¹³The implication is that satisfactory treatment most times requires the use of several drugs acting on various pathways to evoke synergism. Therefore, genes and environment determine whether any drug will work in a particular individual. ¹⁴As a result, it is not surprising that the treatment of hypertension in some patients does not lead to satisfactory control.

The prevalence of resistant hypertension in sub-Saharan Africa in this decade has ranged from 14.3% to 14.6%. In Nigeria in the last decade, it was 4.9%. ⁷ These were all cross-sectional population studies. In Spain, 9.9% of hypertensives in area 6 of Madrid primary care registry had resistant hypertension. ¹⁵The prevalence of apparent and true resistant hypertension here of 58.1% and 54.9% respectively was much higher than the previous report from Nigeria in the last decade and many other series encountered. This is not surprising for two reasons. An epidemiological transition has occurred here, more people are now hypertensive than previously; ¹⁶ and the hypertensives seen in this facility given the specialization mostly had “difficult to control” hypertension. Again, the population in Nigeria is not homogenous. The population referred to in the study of Nanssen et al ⁷ came from a different part of Nigeria; implying that diet, ethnicity, and geography may be different as well. The high prevalence may also be because this is entirely an African population. One common risk factor for having resistant hypertension is African origin. ¹² However, it was possible to control 60% of these resistant hypertensives by optimizing doses and introducing drugs from different classes to bring about synergism. Lifestyle modification and control of some co-morbidities also helped

The extreme phenotype refractory hypertension was seen in 7.1% of the 240 who had resistant hypertension. This is close to the 9.5% recorded by Acelajado et al ¹⁰ in a retrospective study. The same authors in a follow-up prospective study as reported by Dudenbostel et al ¹⁷recorded 3% when denominated by number with uncontrolled resistant hypertension; and for the present study, it was 18.3%. This wide difference may be because of population differences in both studies and the requirement of the use of both Spironolactone and Chlorthalidone in the former before refractory hypertension could be diagnosed. Here the use of Spironolactone alone in the drug cocktail sufficed for the diagnosis of refractory hypertension. In this present study, those with refractory hypertension were mostly in the middle age to elderly categories and were heavier; with co-morbidities prominent of which were metabolic syndrome and diabetes mellitus. There was intense individually volunteered psychological stress in some as well as connective tissue disease co-morbidity. There was a tendency towards having more males in this group.

The prominence of the co-existence of metabolic syndrome in those with uncontrolled hypertension has been documented; and the more metabolic disorders in the spectrum, the worse the control. ¹⁸ Hypertension as part of metabolic syndrome is often resistant to usual pharmacological treatment of hypertension as they have higher chances of developing diabetes mellitus. ¹⁹ The tendency for more males to have refractory hypertension manifested in this study. Gender distribution is inconsistent in other published studies; ²⁰ and may vary with different cohorts based on gender distribution. However, the REGARDS study as reported by Dudenbostel et al ¹⁷ recorded male gender and diabetes as being associated with refractory hypertension. In that same study of Dudebonstel et al, ¹⁷heightened sympathetic activity was more in those with refractory hypertension. Our study had some people under intense psychological stress. This will heighten the sympathetic tone, which is a major contributor to antihypertensive treatment failure. Our finding of refractory hypertension being commoner as patients aged agrees with the study of the MASTERPLAN group. ²¹ As people age, the co-morbidities that make hypertension less amenable to treatment abound. What is peculiar to this cohort is the link between connective tissue disease and refractory hypertension. In connective tissue disease, there is pain that activates sympathetic tone thus raising blood pressure. In addition, vasculitis that usually accompanies the disease causes peripheral constriction that drives elevation of blood pressure. If the process affects the kidneys as they are wont to do, renal vasculitis activates the renin-angiotensin-aldosterone system and cause blood pressure elevation. Until the background connective tissue disease is addressed, it may not be possible to control the blood pressure.

 

Limitations and strengths

 

We were not able to avail patients of ambulatory blood pressure monitoring; which is a better measure of blood pressure burden. Some of our refractory hypertension may be white coat, and without ambulatory blood pressure monitoring, those with masked hypertension will contaminate the data. We also did not take a history of obstructive sleep apnea syndrome. A high prevalence of obstructive sleep apnea syndrome will give rise to a high prevalence of refractory hypertension. Again, we did not consider alcohol history. Patients with evidence of worsening hypertension may be manifesting alcohol withdrawal. ²² However, having excluded secondary causes and sorted out issues related to non-adherence earlier in the cohort is a strength. This was a one-center study as well as being a specialized hypertension service both of which will impair generalization; and affect its external validity.

 

 

CONCLUSION

 

Refractory hypertension should be sought especially in elderly and overweight Africans with co-morbidities. When found, efforts should be devoted to confirming any secondary hypertension. It is also necessary to bear in mind that the difficulty to control blood pressure may be drug-related including antihypertensive in use. Lifestyle intervention goes a long way to help, leaving only a small group who may need device assisted intervention or manipulation of pharmacogenomics.

 

 

Table1

Clinical characteristics of the extreme phenotype of refractory hypertension

 

NOTE: Unit of weight – KG; Unit of duration – Months

                                                                             

KEY: M – Male, F – Female, BP – Blood Pressure, DMD – Disease Modifying Drugs,

CTD – Connective Tissue Disease, OHA – Oral Hypoglycaemic Agents, DM – Diabetes Mellitus, MS – Metabolic Syndrome, NSAID – NON-STEROIDAL ANTI-INFLAMMATORY DRUG, 5PDI – 5 Phospho-Diesterase Inhibitor, ST – Steroid, OAD – Obstructive Airway Disease

BP Drugs 1 – Thiazide, 2 – Calcium Channel Blocker, 3 – Beta Blocker, 4 – Angiotensin Converting Enzyme Inhibitor, 5 – Angiotensin Receptor Blocker, 6 – Aldosterone Inhibitor, 7 – Direct Vaso-Dilator, 8 – Centrally Acting Drug, 9 – Alpha Blocker.

 

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