INTRODUCTION

Hypertension is a growing medical and public health issue around the globe and main cause of disability and mortality. Improving hypertension management remains one of the most difficult task globally. As a result, how to effectively control hypertension based on unique patient characteristics, with non- pharmacological and pharmacological approaches has become problematic and has to be addressed immediately.¹

United States and European treatment guidelines have been issued to attain smooth control of hypertension in different patients. These guidelines, on the other hand, suggest that they may be used to help health care professionals in their routine practice. The final choice for an individual patient must be made by skilled health professionals in consultation with the caregiver and patient, if appropriate.²

When mean diastolic blood pressure (MDBP) is ≥ 90 mmHg and mean systolic blood pressure (MSBP) is ≥ 140 mmHg, it is classified as stage 2 hypertension. The 7^th report of the Joined National Committee on prevention, detection, and treatment of hypertension recommends that individuals with stage 2 hypertension need to be treated with a combination of two drugs from different classes.³

According to literature, fixed-dose combinations are more effective, well tolerated, safe, and cost effective than monotherapy. Yet further studies are needed to determine the best combination therapy for diverse groups based on race, gender, age, and comorbidities.⁴

Blood pressure should be monitored regularly. Angiotensin-converting enzyme inhibitors (ACEIs) or Angiotensin II receptor blockers (ARBs) should be used in conjunction with calcium channel blockers (CCBs) or thiazide diuretics, according to European hypertension guidelines.⁵ According to these guidelines replacing hydrochlorothiazide with amlodipine

had many metabolic and cardiovascular benefits.⁶ In another trial, losartan and amlodipine were found to be more effective at regulating blood pressure (BP) than losartan and hydrochlorothiazide⁷.

In a clinical trial, Kondo et al. found that combining telmisartan and amlodipine or telmisartan and hydrochlorothiazide reduced BP effectively in patients with uncontrolled hypertension previously receiving angiotensin II receptor blocker only .⁸

In a study from Africa reported that either perindopril or hydrochlorothiazide with amlodipine were more effective than perindopril plus hydrochlorothiazide in decreasing blood pressure after 6 months of treatments.⁹ Hypertension is a very common disease, so general physicians need to familiarize themselves with best practices in blood pressure control to become better advocates of evidence-based medicine.

Hence, the study was designed to determine the efficacy of valsartan and hydrochlorothiazide versus valsartan and amlodipine along with the safety and tolerability of both combinations.

MATERIALS AND METHODS

This experimental study was carried at Medicine Department of Shalamar Hospital Lahore. Purposive sampling technique was used. Ethical approval was granted by Institutional Review board of Shalamar Medical & Dental College, Lahore. 126 patients with stage 2 hypertension having BP≥140/90 mm Hg were recruited from medical outdoor of Shalamar Hospital after getting informed consent. The patients were randomly allocated to group A and group B. Both groups included the patients from both genders aged 35-65 years, having stage 2 hypertension with MDBP ≥ 90 mmHg and MSBP ≥140 mmHg in sitting position.³

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The patients who had secondary hypertension, hypertensive crises, advanced heart failure, renal or hepatic disease, past history of myocardial infarction, stroke, transient ischemic attack, or angioplasty in last six months and taking more than two antihypertensive drugs were excluded from the study.

Baseline blood pressure was recorded at day "0" and 5 ml venous blood was drawn for laboratory investigations of biochemical parameters before prescribing the combination therapy. In group A, 63 patients were prescribed oral valsartan and hydrochlorothiazide 160/12.5 mg once daily. In group B, 63 patients were prescribed oral valsartan and amlodipine 160/5 mg once daily. Patients were advised to come for follow up of BP, laboratory investigations and side effects at 2^nd, 4^th, and 8^th week.

The British Hypertension Society (BHS) guidelines were followed for taking blood pressure readings. The patients were asked to avoid smoking or consuming coffee about 30 minutes before recording of blood pressure. A mercury sphygmomanometer was used to record three readings blood pressure and then average of the three readings was calculated.¹¹

Blood samples were collected and reported by Shalamar Hospital laboratory.

The efficacy variables in both groups, to assess the equivalence of therapeutic efficacy of the two regimens are:

• the change in mean sitting systolic blood pressure (MSBP)

• the change in mean sitting diastolic blood pressure (MDBP)

• Control rate defined as the proportion of patients achieving mean diastolic blood pressure ≤90 mmHg ^12,13.

   

   

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  Safety was determined by exploring the side effects (either reported by patients or asked by the physicians), clinical examination, and laboratory reports on 2^nd, 4^th and 8^th week.

  Statistical Analysis

  The data was analyzed by SPSS version 22.Comparison between two groups was done by applying t-test and Chi square ( ²) test accordingly p-value ≤ 0.05 was taken as significant.

  RESULTS

  Mean age of patients in group A and B was 52

  ± 10 and 53±09 years respectively. In group A 68% patients were female and 32% were male while in group B 83% patients were female and 17 % were male. Mean weight of patients in group A was 76±18 kg and in group B was 75±19 kg body weight.

  Efficacy analysis of both groups showed that both combinations were effective in controlling blood pressure. Baseline BP was recorded in both groups. Baseline MSBP and MDBP in group A were 160.9 ±14 and 94.8 ±6 mmHg respectively. In group B, MSBP and MDBP were 151.7±13 and 91.2±7 mmHg respectively.

  In both groups there was a decrease in systolic and diastolic BP on each visit as shown in table 1 and 2 respectively.

  In group A taking valsartan and hydrochlorothiazide, there was 39±7 and 18±1 decrease in MSBP and MDBP from base line respectively. While in group B taking valsartan and amlodipine, there was 26.7±4 and 14±2 decrease in MSBP and MDBP from base line respectively (Table 1).

  Efficacy of treatment in reducing MSBP was 100% and 97.6% (p=0.47) in group A and group B respectively) after 8 weeks of treatment and this reduction in MDBP was 100% (p=0.99).in both groups (Table 2). significant statistically.

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  Variables Groups A (mean±SD)

  Groups B (mean±SD)

  P-

  value

  Baseline Systolic BP 160.9±14 151.7±13 0.01*

  Diastolic BP 94.8±6 91.2±8

  2

  weeks(mean±SD) 4

  weeks(mean±SD) 8

  weeks(mean±SD)

  Systolic BP 133.8±13 137.4±16

  Diastolic BP 84.4±8 84.7±7

  Systolic BP 125.8±10 128±10

  Diastolic BP 78.9±8 79±7

  Systolic BP 121.9±7 125±9

  Diastolic BP 76.7±5 77±6

  0.03*

  0.27

  0.85

  0.23

  0.96

  0.06

  0.07

  Decrease in SBP on 8th week from Baseline

  Decrease DSBP in 8th week from Baseline

  39±7 26.7±4 0.47

   

   

  18±1 14±2 0.66

  t-test was applied; p<0.05considered statistically significant

   

   

   

   

  Groups	SBP <140 mmHg Yes No		p-value	Yes	DBP ≤90 mmHg No		p-value
  A	63(100%)	0		63(100%)		0
  B	61(97.6%)	2(2.4)	0.47	63(100%)		0.99 0

  Chi-square test was applied; P<0.05 considered statistically significant

   

   

   

  _{Figure 1: Comparison of MDBP between two groups} Figure 2: Comparison of MSBP between two groups

   

   

   

   

   

   

  Level of serum	0 week	Group A 8 week	p-value	0 week	Group B 8 week	p-value
  Sodium(mmol/l	(mean±SD) 138.8±3.7	(mean±SD) 138.5±2.4	0.41	(mean±SD) 139.4±3.4	(mean±SD) 139.1±2.5	0.43
  Potassium(mmol/l)	4.21±0.4	4.81±0.5	0.95	4.20±0.5	4.20±0.5	0.83
  Chloride(mmol/l)	100.5±3.9	100.7±3.6	0.83	99.3±2.4	99.3±2.4	0.41
  Creatinine(mg/dl	0.86±0.2	0.93±0.3	0.06	1.03±0.5	0.96±0.6	0.058
  cholesterol(mg/dl	150.1±36.1	150.7±42.1	0.10	175.1±33.8	175.5±28.3	0.20
  Sugar(R) (mg/dl)	151.0±51.2	153.0±36.2	0.053	145.9±41.1	146.1±32.5	0.31
  Urea(mg/dl)	3.53±0.7	3.70±0.8	0.33	3.5±0.7	3.6±0.8	0.58

   

  0 = No case reported

   

   

  Side effects Groups	0 Week A	B	2nd Weeks A	B	4th Weeks A	B	8th Weeks A	B
  	(%)	(%)	(%)	(%)	(%)	(% )	(%)	(% )
  Pedal oedema	0	0	5	10	5	15	0	15
  Cough	0	0	8	6	6	1	0	0
  Headache	0	3	18	16	11	2	1	0
  myalgia	1	3	16	10	15	1	3	0
  Diarrhoea	0	0	1	1	1	0	0	0
  Lethargy	1	0	11	14	11	2	1	0
  Rash	0	0	0	0	0	0	0	0

   

  Safety and tolerability were assessed by appearance of side effects and derangement of biochemical parameters a shown in table 3 & 4 respectively. In either of the combination headache, myalgia, lethargy, cough, and edema was noted in few patients in 2nd and 4th week but it disappeared on 8th week in all the patients. But the edema persisted in 15% patients taking valsartan and amlodipine till 8th week.

  Myalgia was observed in very few patients taking valsartan and hydrochlorothiazide combination (3%). There was no significant derangement of biochemical parameters in both groups.

  DISCUSSION

  The blood pressure lowering effect of valsartan, when paired with hydrochlorothiazide or amlodipine, as first choice hypertension therapy was evaluated and compared in this study. According to a meta- analysis, combination therapy provides smooth blood pressure regulation, fewer side effects, and better tolerance in hypertensive patients than monotherapy.¹⁴

  Both combinations are recommended by JNC, but it has been suggested that further research is required to finalize choice of combination therapies in different populations based on race, gender, and age. So, it was observed in this study that both combinations are effective

  for smooth control of blood pressure in our

  population. These result are in accordance with study of Poldermas et al., which found that combinations of amlodipine and valsartan was well tolerated and more effective.¹⁵ In our study efficacy of valsartan and hydrochlorothiazide was not found to be significantly higher than valsartan and amlodipine combination, which is contradictory with a study done by Habeel et al; in 2017.¹⁶ The current study demonstrates that the fixed-dose combination of valsartan and hydrochlorothiazide was safer and better tolerated.

  The patients who received combination of valsartan and hydrochlorothiazide had more complains of headache, lethargy and myalgia when compared with patients taking valsartan and amlodipine in first two weeks. However, combination of amlodipine and valsartan also showed edema, headache, and myalgia in first two weeks, but these side effects decreased on 8th week except peripheral edema which persisted even after 8 weeks. This high incidence of peripheral edema with amlodipine combination was also observed in another study by Zappe et al.¹⁷

  In present study edema disappeared in the group taking valsartan and hydrochlorothiazide, which is consistent with the findings of Matthew.et.al. According to their study angiotensin receptor blockers and angiotensin-converting enzyme inhibitors cause post-capillary dilation and normalize hydrostatic pressure, making them ideal for preventing/reversing calcium channel blocker- induced edema¹⁸. In present study it was found that combination of Valsartan and Hydrochlorothiazide is better tolerated than combination of valsartan and amlodipine.¹⁹

  It was a single-center study, which may have reduced the chances of identifying the genuine benefits of those therapies.

  CONCLUSION

  Both combinations are effective for control of BP, but valsartan and hydrochlorothiazide combination appear to be more effective in decreasing BP and better tolerated as compared to combination of valsartan and amlodipine.

  Recommendations

  The current study looked at 'soft' endpoints and was non-inferiority based, thus more

  Research is needed to see which sort of valsartan-based combination is superior in big samples from different centers of the country.

  Conflicts of interest

  All authors declared no conflicts of interest.

  Source of funding

  Shalamar Medical and Dental College provided funds and necessary support.

  Acknowledgements

  Authors are grateful to all postgraduate residents and statistician of college who participated in this study.

  Contributors

  AK: Study design, manuscript writing. revised and approved the article.

  SI: Primary drafting, data analysis and result MRA: entered, analyzed, and interpreted data SAB: contributed to writing of literature review MN & MA: Data collection, result, discussion All authors approved the final version and signed the agreement to be accountable for all aspects of work.

  REFERENCES

• Hong D, Shan W. (2021).Improvement in Hypertension Management with Pharmacological and Non- Pharmacological Approaches: Current Perspectives. Curr Pharm Des. 2021; 27(4): 548-555

• Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M, et al. ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and

   

   

  125 J Shalamar Med Dent Coll Jan-June 2022 Vol 3 Issue 1

  the European Society of Hypertension (ESH) Eur Heart J. 2018; 39(33): 3021–3104

• Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Cheryl DH, et al. Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2018; 71 (19): 127–e248

• Rochlani Y, Khan MK, Banach M, Aronow WS. Are two drugs better than one? A review of combination therapies for hypertension, Expert Opin Pharmacother. 2017; 18(4): 377- 386

• Volpe M, Tocci G. Rationale for triple fixed- dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic. Vasc Health Risk Manag. 2012; 8: 371-380

• Buscemi S, Buscemi C, Borzì AM, Cosentino L ,Rosafio G ,Randazzo C, Colomba D, et al. Metabolic and Cardiovascular Effects of Switching Thiazides to Amlodipine in Hypertensive Patients With and Without Type 2 Diabetes (the Diuretics and Diabetes Control Study. Metab Syndr Relat Disord. 2020; 18(2): 110-118

• Cho EJ, Lee HY, Sung KC, Park S, Sohn IS, Park CG, et al. Comparison of 24-Hour Ambulatory Central Blood Pressure Reduction Efficacy Between Fixed Amlodipine or Up-Titrated Hydrochlorothiazide Plus Losartan: The K- Central Study. Am J Hypertens. 2019; 32(10): 992-1002.

• Kensuke K, Ryuji T, Tatsuro I, Kenta M, Tomoyuki Y, Kenichi H. Comparison of telmisartan/amlodipine and telmisartan/hydrochlorothiazide in the treatment of Japanese patients with uncontrolled hypertension. Blood Press Monit. 2016; 21(3): 171-177

• Ojji DB, Mayosi B, Francis V, Badri M, Cornelius V, Smythe W, et al. Comparison of Dual Therapies for Lowering Blood Pressure in Black Africans. N Engl J Med. 2019; 380(25): 2429-2439

• Flight L, Julious SA. Practical guide to sample size calculations: non-inferiority and equivalence trials. Pharm Stat. 2016; 15(1): 80-89

  J Shalamar Med Dent Coll Jan-June 2022 Vol 3 Issue 1

• Stergiou G, Palatini P, Asmar R, de la Sierra A, Myers M, Shennan A, Wang J, O'brien E, Parati G. Blood pressure measurement and hypertension diagnosis in the 2017 US guidelines: first things first. Hypertension. 2018; 71(6): 963-965.

• Rakugi H, Kario K, Yamaguchi M, Sasajima T, Gotou H, Zhang J. Efficacy of sacubitril/valsartan versus olmesartan in Japanese patients with essential hypertension: a randomized, double-blind, multicenter study. Hypertens Res. 2022; 45(5): 824-833

• Humagain S, Koju R. Efficacy of Different Antihypertensive Drugs among newly Diagnosed Hypertensive Patient in Dhulikhel Hospital. Kathmandu Univ Med J. 2015; 13(51): 212–215

• Lv Y, Zou Z, Chen GM, Jia HX, Zhong J, Fang WW. Amlodipine and angiotensin- converting enzyme inhibitor combination versus amlodipine monotherapy in hypertension: a meta-analysis of randomized controlled trials. Blood Press Monit. 2010; 15(4): 195-204

• Poldermans D, Glazes R, Kargiannis S, Wernsing M, Kaczor J, Chiang YT, et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage-2 hypertension. Clin Ther. 2007; 29(2): 279-289

• Dar MH , Falah SF , khan I , khan A, Ali U. Efficacy of valsartan plus amlodipine versus valsartan plus hydrochlorothiazide for control of moderate to severe hypertension: a randomized controlled trial. Pak Heart J. 2017; 50 (01) : 39-44

• Zappe D, Papst CC, Ferber P, PROMPT Investigators.(2009). Randomized study to compare valsartan +/- HCTZ versus amlodipine +/- HCTZ strategies to maximize blood pressure control. Vasc Health Risk Manag. 2009; 5: 883–892

• De la Sierra A. Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin–angiotensin system. Journal of human hypertension. 2009; (8): 503-511.

• Weir MR, Ferdinand KC, Flack JM, Jamerson KA, Daley W, Zelenkofske S. A

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  noninferiority comparison of valsartan/hydrochlorothiazide combination versus amlodipine in black hypertensives. Hypertension. 2005; 46(3): 508-513.

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

   

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