Developing practical recommendations for drug-disease interactions in patients with hypertension

Background: Hypertension, a significant risk factor for cardiovascular diseases, demands proactive management as cardiovascular diseases remain the leading cause of death worldwide. Reducing systolic and diastolic blood pressure levels below recommended reference values of <140/90 mmHg can lead to a significant reduction of the risk of CVD and all-cause mortality. However, treatment of hypertension can be difficult and the presence of comorbidities could further complicate this treatment. Drugs used to manage these comorbidities may inadvertently have an impact on blood pressure, resulting in a phenomenon known as drug-disease interaction. This study aims to assess the safety of medication that can affect blood pressure in patients with hypertension and provide practical recommendations for healthcare professionals. Methods: For the development of recommendations for the drug-disease interaction (DDSI) hypertension, a six-step plan that combined literature selection and multidisciplinary expert opinion was used. The process involved (1) defining the scope of the DDSI and selecting relevant drugs, (2) collecting evidence, (3) data-extraction, (4) reaching of expert consensus, (5) publication and implementation of the recommendations in healthcare systems and (6) updating the information. Results: An increase of 10 mmHg in systolic blood pressure and 5 mmHg in diastolic blood pressure was defined as clinically relevant. Corticosteroids, danazol, and yohimbine caused a clinically relevant DDSI with hypertension. Several other drugs with warnings for hypertension in the official product information were assessed to have no clinically relevant DDSI due to minor influence or lack of data on blood pressure. Drugs with evidence for a relevant change in blood pressure which are prescribed under close monitoring of blood pressure according to clinical guidelines, were deemed to be not clinically relevant for signalling. Conclusion: This study provides specific recommendations that can be implemented directly in clinical practice, for example, in clinical decision support systems, potentially resulting in safer drug use in patients with hypertension and better healthcare by reducing alert fatigue. Future research should focus on evaluating the effectiveness of implementation strategies and their impact on reducing unsafe use of medication in patients with hypertension.


CONCLUSIONS
Corticosteroids can cause hypertension or worsen existing hypertension.This is especially the case in doses higher than 7.5 mg prednisolone or equivalent doses or in drugs with a pronounced mineralocorticosteroid effect.It is possible that the rise in blood pressure is less prominent in patients already taking antihypertensive drugs.

OTHER REMARKS
Mineralocorticosteroids act on the distal renal tubules and promote reabsorption of water and salt, thereby increasing blood pressure.Glucocorticosteroids have mineralocorticosteroid potency as well, but in varying degrees.Other blood pressure-increasing effects of corticosteroids include: -Redistribution of body fluids with increased plasma volume and increased cardiac output -Increased sensitivity of blood vessels to catecholamines -Activation of the central and peripheral nervous system -A direct effect on smooth muscle tissue of blood vessels Cortisone, hydrocortisone and fludrocortisone have a pronounced mineralocorticosteroid effect in addition to glucocorticosteroid action.The other corticosteroids have only limited mineralocorticosteroid potential.

Clinical relevance
Change in blood pressure was the main outcome of interest during assessment.Increases in blood pressure of 10 mmHg SBP and 5 mmHg DBP were considered clinically relevant.In patients with risk factors, an increase of 5 mmHg SBP was considered clinically relevant.

OTHERnot compliant with PICO
There were no studies that complied with PICO.The following studies described the effect of corticosteroids on blood pressure in normotensive patients.

Results
• Of 398 patients with rheumatoid arthritis, 70% of whom had hypertension, 281 used no or limited prednisolone, 58 used longterm low-dose prednisolone (< 7.5 mg/day, > 6 months) and 59 used long-term medium-dose prednisolone (7.5-30 mg/day, > 6 months).The latter group used an average of 9.17 mg prednisolone per day at the time of study.

Results
• Database study on the influence of DMARDs on blood pressure in veterans with rheumatoid arthritis (RA).Prednisone (n = 10,027, 76% with hypertension) was one of the studied DMARDs.Blood pressure was determined 6 months before treatment initiation, just after and 6 months after.• The percentage of patients with blood pressure <130/90 mmHg was greater 6 months after starting the DMARD than at baseline (50.0% vs. 47.3%, p <0.001).A similar trend was seen for prednisone (p < 0.0001).• There was a limited decrease in systolic and diastolic blood pressure 6 months after start of 1.67 and 0.60 mmHg, respectively (p < 0.05).In the subgroup with patients not taking antihypertensive drugs, there was only a significant decrease in systolic blood pressure, estimated at 0.75 mmHg (p < 0.05).• A clinically relevant increase in blood pressure was seen more frequently with prednisone than with methotrexate (OR 1.18; 95%CI 1.10 to 1.27).A clinically relevant increase was described as >20 mmHg SBP or >10 mmHg DBP.The risk for hypertension was also greater with prednisone compared to methotrexate (HR 1.30; 95% CI 1.08 to 1.56).

Remarks authors
• Treatment with DMARDs leads to a decrease in blood pressure after starting treatment.This is also true for prednisone.In patients with RA, prednisone may have a beneficial effect on blood pressure because it inhibits RA-induced inflammation.

Remarks assessors
• Of the patients on prednisone, 73% were treated with an antihypertensive before starting prednisone.It is not known whether the dose of this antihypertensive was adjusted after starting prednisone.• The dose of prednisone was not reported.Bloechliger M et al.

Results
• For each side effect of corticosteroids in asthmatics, a separate cohort and case-control study were performed in this database asthma patients in the UK: cohort study with a nested case-control analysis.

Respiratory Research 2018;19:75
Retrospective cohort study study.One of the adverse events was the occurrence of hypertension, defined as a diagnosis code for hypertension and a prescription for an antihypertensive drug.
• In almost all cases, prednisolone was used as a corticosteroid.The incidence rate ratio (IRR) for hypertension was increased for prednisolone users (IRR 1.2; 95%CI 1.2 to 1.3) and former users (IRR 1.4; 95%BI 1.3 to 1.4) compared with patients who never used prednisolone.However, after adjusting for confounders, the case-control study found no association between prednisolone use and hypertension.

Remarks authors
• Other studies did find a significant association.This was not the case in this study, perhaps due to the definition of hypertension (both indication code and antihypertensive drug).

Remarks assessor
• Patients in the cohorts with continuous use were older than those with intermittent use.In addition, the prevalence of conditions differed in the cohorts, so confounding by indication cannot be ruled out.Also, no control group was included in this study.

Results
• Cohort study of the influence of corticosteroids on blood pressure in the first 3 months after corticosteroid initiation.• In patients treated with antihypertensive therapy before corticosteroid initiation, no increase in blood pressure was seen.
In patients without antihypertensive therapy, a clinically irrelevant increase in SBP was seen (increase <1 mmHg, p = 0.03).No increase was seen for DBP (p = 0.52).• Among patients without antihypertensive therapy, 10% had a rise in SBP >20 mmHg and 4% had a rise ≥30 mmHg.A similar number of patients had such a decrease in blood pressure.• Patients with a large increase were older, thinner and had a history of hypertension.In addition, they were treated with prednisone/prednisolone more often.

Remarks authors
• In the first three months of use, blood pressure increase with corticosteroids is not clinically relevant.The risk of extreme blood pressure rise is higher with prednisone/prednisolone, probably due to the high mineral corticoid potency.

Remarks assessor
• Patients on antihypertensive therapy were not studied further because little variation in blood pressure was seen.

Results
• In this retrospective study in Malaysia, an association between hypertension and long-term corticosteroid use was seen in patients with lupus nephritis (n=82).In patients with hypertension (n= 55), the cumulative dose was 25.25 g (IQR 22.6 g) and in patients without hypertension 12.5 g (IQR 14.1 g) (p < 0.001).The duration of treatment with corticosteroids was 6.8 years (IQR 6.7 years) in patients with hypertension versus 3.25 years (IQR 3.9 years) in patients without hypertension (p <0.05).

Review
Human studies are small and often lack a control group.200 mg hydrocortisone for 1 week in 8 healthy volunteers gave an increase in blood pressure.40 mg/day i.v.prednisolone along with methylprednisolone, triamcinolone and dexamethasone in equivalent doses was administered for 5 days in 6 healthy volunteers.Systolic blood pressure increased 6-13 mmHg and diastolic 7-11 mmHg.In a retrospective study of 195 rheumatoid arthritis patients taking prednisone (< 20 mg/day) for more than 1 year, no blood pressure change occurred.Blood pressure rise is mainly dependent on dosage, not on duration of therapy.De Leeuw PW.Druginduced hypertensionrecognition and management in older patients.Drugs&Aging 1997;11(3):178-185

Review
Fludrocortisone may cause a sharp rise in blood pressure, especially in patients with pre-existing orthostatic hypertension and the elderly.Blood pressure rise has also been seen after intranasal use.The effect is reversible.

Reference Results/remarks
Dutch guidelines [1][2][3][4][5] Glucocorticosteroids could increase the risk for hypertension in several patient populations.At the start of treatment, regular control of blood pressure is indicated. [

Special warnings and precautions for use
Because of the possibility of fluid retention, care must be taken when corticosteroids are administered to patients with renal insufficiency or hypertension or congestive heart failure.
Corticosteroids may worsen diabetes mellitus, osteoporosis, hypertension, glaucoma and epilepsy and therefore patients with these conditions or a family history of them should be monitored frequently.

Special warnings and precautions for use
Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.
[…] Hypertension SPC Fludrace 08-08-2017 4.4 Special warnings and precautions for use Special caution must be observed in patients who seem to be predisposed to developing complications on the basis of hypertension Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

2 Supplementary Data -Translated assessment report Hypertension: corticosteroids
The prevalence of hypertension was significantly higher in the medium-dose prednisolone group (84.7%) than in the no-or limited-dose prednisolone group (67.3%) and the low-dose prednisolone group (70.7%).•The OR for hypertension was increased for the group with medium-dose prednisolone compared with the group with no or limited-dose prednisolone.

•
Patients on pulse methylprednisolone treatment actually had lower systolic and diastolic blood pressure.Systolic blood pressure increases by about 15 mmHg with a dose of 80-200 mg/day of cortisol (or equivalent).It may occur within 24 hours.However, no increase in blood pressure occurs at 40 mg/day.