Nuts and Bolts of latest Hypertension Guidelines - The emphasis on combination therapy

Hypertension, marked as a disorder with invading effects, shows increasing prevalence in different forms all across the globe. For example, in India alone, 30% of the population has high blood pressure, which shockingly conveys that 1/3rd of the adult population is hypertensive.

Surprisingly, the cornerstone of prevention and treatment is not drugs but dietary intake and lifestyle. Sodium intake plays a significant role in hypertension. High sodium intake is a significant contributor to salt sensitivity, more frequently observed in the elderly population. Since the Indian population follow a high sodium diet intake, the elderly population is prone to hypertension.

Hence, it is critical to maintaining low sodium levels, mainly if the patient is prescribed with Angiotensin-Receptor Blockers (ARBs), ACE-inhibitors as high sodium levels can suppress the action of these drugs.

The critical steps for proper BP measurements include(3)

- Step 1: Prepare the patient properly.

- Step 2: Use proper technique for BP measurements.

- Step 3: Take the proper measurements needed for diagnosis and treatment of elevated BP/hypertension.

- Step 4: Properly document accurate BP readings.

- Step 5: Average the readings.

- Step 6: Provide BP readings to patient.

Failure in taking precautions, hypertensive patients are at risk of getting wrong/falsely high measurements and misdiagnosing hypertension.

The table below compares the European Guidelines of Hypertension with the American Guidelines of Hypertension.(4)

If a patient is at risk of high cardiovascular events or possesses a 10-year cardiovascular profile, then the blood pressure range should be 130/80 mmHg. However, patients falling out of that category are marked safe provided their blood pressures is maintained below 140/90 mmHg.

Perfect BP control is a function of 24-hour BP reduction, early morning BP surge, nocturnal dipping and BP variability.5 Calcium blockers reduce blood pressure variability.5 ACE-inhibitors can also carry out this function provided the patient is on a low sodium diet.(5)

Every 10/5mm increase in 24hr SBP / DBP increases the combined risk of cardiovascular mortality, ischemic heart disease and stroke.(6)

As evident from the table, Telmisartan shows a considerably longer half-life as compared to other ARBs.

In the case of diuretics, Chlorthalidone beats other diuretics with a half-life of 40 hours. For ACE-inhibitors, Perindopril stands apart with a comparatively longer half-life of 17 hours. Similarly, in beta-blockers, Bisoprolol and Nebivolol show a longer half-life of 12 and 10.3 and 31.9, respectively. Lastly, for CCBs, Amlodipine has a longer half-life of 30-55 hours. With these drugs in line, a significant difference can be observed after two to three weeks.

Telmisartan & Amlodipine have the highest smoothness index compared to other antihypertensive agents.(7) Higher smoothness index indicates smoother 24-h BP reduction profile.(7) (Smoothness Index: consistency of BP control over the 24-hr period.)

In a large study conducted on elderly patients (men only) on monotherapy, it was found that around 40% to 50% of the patients showed less than 70% response to monotherapy.(8,9) Telmisartan was shown to reduce the progression of nephropathy compared to no treatment.(8,9)

AMADEO Trial focusing on albuminuria and blood pressure included patients with diabetic kidney disease.10 The inclusion criteria was:(10)

- Type 2 diabetes

- Hypertension (seated SBP/DBP >130/>80 mmHg)

- Macroproteinuria (>700 mg/g creatinine (the first morning voided urine), equivalent to 900 mg/24 hours)

- Serum creatinine

• women <265 µmol/L (<3.0 mg/dL)

• men <285 µmol/L (<3.2 mg/dL)

Patient Baseline Characteristics

Study Design

The main aim of this clinical trial was to get the blood pressure less than 130/80mmHg.10 Post 1 year, the results conveyed a clear difference in albuminuria by 30% with Telmisartan, whereas Losartan showed a reduction of 21.4% in albuminuria.(10) Telmisartan was also found to be effective in terms of blood pressure and sodium excretion.(10) The systolic blood pressure showed a considerable difference, and it was not influenced by sodium excretion.

Telmisartan's more prolonged action, greater intensity of binding receptors gives an edge to it over other drugs.

The rationale for Single-Pill Combination Therapy: Background

• Traditional antihypertensive therapy yields goal BP in <60% of treated hypertensive patients.(11,12,13)
• Switching from one monotherapy to another is effective in only about 50% of patients.(11)
• Most patients will require at least two drugs to attain goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic renal disease) (14,15,16)

Adults with stage 2 hypertension and an average blood pressure more than 20/10mmHg above their BP target should begin antihypertensive drug therapy with two first-line agents of different classes, either as separate agents or in a fixed-dose combination.(18)

Another drug or doubling the monotherapy dosage can invite various side effects, as shown by a classic study in which hypertensive patients on different monotherapy doses were doubled.(19)

Conclusion

• Fixed-dose combinations are essential in hypertension treatment. Hence most patients suffering from hypertension require a fixed-dose combination, mainly because of compliance and adherence.
• Adults with stage 2 hypertension and an average blood pressure more than 20/10mmHg above their BP target should begin antihypertensive drug therapy with two first-line agents of different classes, either as separate agents or in a fixed-dose combination
• The doses should be decided logically according to the severity of hypertension, and lastly, the best of the classes must be chosen to assure efficacy.
• Preferable CCB is amlodipine for its long-acting PK and telmisartan among ARBs
• ABPM data is still evolving and presently its expensive.
• For pedal edema there is not much difference, as class effect data is lacking and Japanese trials have small number of subjects to generalize.

Key Messages

1. Updated Hypertension Guidelines continue to emphasize combination therapy, especially with the most efficacious drugs within a class and adherence with drugs and lifestyle.

2. Usage of dihydropyridine CCBs + RAS blocker plus appropriate diuretics is preferred.

3. Spironolactone should be considered as the fourth drug after diuretics, CCB and RAS blockers.

References

1. Singh AK, Farag YMK, Mittal BV, Subramanian KK, Reddy SRK, Acharya VN, et al. Epidemiology and risk factors of chronic kidney disease in India - results from the SEEK (Screening and Early Evaluation of Kidney Disease) study. BMC Nephrol. 2013;14(1):114.

2. [cited 2021 Jun 15]. Available from: http://s://www.nature.com/articles/nnano.2007.172 #citeas

3. ACC/AHA BP Guidelines Hypertension 2018

4. Bakris G, Ali W, Parati G. ACC/AHA versus ESC/ESH on hypertension guidelines: JACC guideline comparison. Journal of the American College of Cardiology. 2019 Jun 18;73(23):3018-26.

5. Kario K. The HOPE Asia Network activity for "zero" cardiovascular events in Asia: Overview 2020. The Journal of Clinical Hypertension. 2020 Mar;22(3):321-30.

6. Hansen TW, Jeppesen J, Rasmussen S, Ibsen H, Torp-Pedersen C. Ambulatory blood pressure monitoring and risk of cardiovascular disease: a population based study. American journal of hypertension. 2006 Mar 1;19(3):243-50.

7. Parati G, Schumacher H. Blood pressure variability over 24 h: prognostic implications and treatment perspectives. An assessment using the smoothness index with telmisartan–amlodipine monotherapy and combination. Hypertension Research. 2014 Mar;37(3):187-93.

8. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J. Angiotensin-receptor blockade versus converting–enzyme inhibition in type 2 diabetes and nephropathy. New England Journal of Medicine. 2004 Nov 4;351(19):1952-61.

9. Barnett A. Preventing renal complications in type 2 diabetes: results of the diabetics exposed to telmisartan and enalapril trial. Journal of the American Society of Nephrology. 2006 Apr 1;17(4 suppl 2):S132-5.

10. Kalaitzidis R, Bakris GL. Eects of angiotensin II receptor blockers on diabetic nephropathy. Journal of Hypertension. 2009 Jul 1;27:S15-21.

11. Kalaitzidis R, Bakris GL. Eects of angiotensin II receptor blockers on diabetic nephropathy. Journal of Hypertension. 2009 Jul 1;27:S15-21.

12. Gasbarro R. Hypertension: the use of combination therapy (peer-reviewed review article).

13. Chalmers J, Tiller D, Horvath J, Bune A. Eects of timolol and hydrochlorothiazide on blood-pressure and plasma renin activity. Double-blind factorial trial. Lancet (London, England). 1976 Aug 1;2(7981):328-31.

14. Mitka M. DASH dietary plan could benefit many, but few hypertensive patients follow it. JAMA. 2007 Jul 11;298(2):164-5.

15. Cifkova R, Erdine S, Fagard R, Farsang C, Heagerty AM, Kiowski W, Kjeldsen S, Luscher T, Mallion JM, Mancia G, Poulter N. Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertens. 2003 Oct 1;21(10):1779-86.

16. American Diabetes Association. Management of Diabetes in Correctional Institutions. Diabetes Care. 2002 Jan 1;25(suppl 1):s120-1.

17. Gradman AH, Basile JN, Carter BL, Bakris GL, American Society of Hypertension Writing Group. Combination therapy in hypertension. The Journal of Clinical Hypertension. 2011 Mar;13(3):146-54.

18. Aronow WS. Initiation of antihypertensive therapy. Annals of translational medicine. 2018 Feb;6(3).

19. Shantsila A, Lip GY. Combining 2 classes of blood pressure–lowering drugs has an approximately additive eect on systolic blood pressure. Annals of internal medicine. 2009 Aug 18;151(8):JC2-11