Peer Review Report. [Fixed Dose Combination Lisinopril + Hydrochlothiazide]

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Gwenda Wiggins
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1 21 st Expert Committee on Selection and Use of Essential Medicines Peer Review Report [Fixed Dose Combination Lisinopril + Hydrochlothiazide] (1) Does the application adequately address the issue of the public health need for the medicine? Arterial Hypertension is a highly prevalent disease, with estimates reaching 26% of the worldwide adult population as defined by a systolic blood pressure (BP)of 140mmHg or higher, a diastolic BP of 90mmHg or higher, or currently using BP-lowering drugs. HTN remains one of the major preventable risk factors for coronary events, cerebro-vascular disease, heart failure, peripheral vascular disease and progression of kidney disease. Most patients with hypertension will require more than one drug to achieve Blood Pressure target, and monotherapy would only be sufficient in about 20 30% of patients. In addition, around 24% to 32% of patients will require a combination of more than two drugs to achieve BP targets. In a recent meta-analysis, a target systolic BP of less than 130 mmhg significantly decreased the incidence of cardiovascular events, and in the recently published SPRINT trial, a mean number of Blood Pressure medications of 2.8 was required to achieve a mean systolic Blood Pressure of 121.5mmHg in the intensive treatment group, which resulted in a 25% lower relative risk of cardiovascular events as compared to the standard-treatment group. (2) Have all important studies/evidence of which you are aware been included in the application? Please provide brief comments on any relevant studies that have not been included: Samir G. Mallat et al a systematic review and meta-analysis of existing data from RCTs has demonstrated low quality evidence available of a fixed drug combination versus a free drug combination, however, the study does not confirm or rule out a significant difference between using a fixed drug combination versus a free drug combination, with respect to blood pressure control and incidence of adverse events, in the management of hypertension. Moreover, the included studies in the review didn t adequately assess the effect on compliance and rapidity in achieving blood pressure targets, however the available evidence suggests a trend towards better compliance and a more rapid achievement of blood pressure targets, what remained to be confirmed if these effects could be translated into a great impact at reducing cardiovascular morbidity associated with hypertension. However, due to overall high risk of bias and low quality of trials included, the results of this systematic review should be interpreted cautiously.

2 Samir G. Mallat et al (1) has contributed body of literature to substantiate lack of high quality evidence to support the superiority of one approach to combination therapy over the other in the management of hypertension. There is a need for additional Randomized Clinical Trials, with long follow-up and assessment cardiovascular and mortality outcomes, to better guide clinical practice. Previously published systematic reviews on the subject favoured the use of fixed combination therapy in the management of hypertension. In an analysis of 15 retrospective studies, Sherrill et al. demonstrated increased adherence and persistence to therapy with subsequent reduced healthcare costs with the use of a fixed combination regimen (2). In another systematic review, Gupta et al demonstrated a significant improvement in compliance, and nonsignificant trends in Blood Pressure control and adverse events favoring the use of a fixed combination (3). Samir G. Mallat et al review differs from these systematic reviews (Sherrill et al & Gupta et al) in few aspects; First, strictly included randomized clinical trials. Second, used rigorous methodology for assessing the included trials for risk of bias, i.e., the Cochrane Collaboration Risk of Bias tool. Third, assessed the quality of evidence by outcome using the GRADE methodology. Sherrill et al and Gupta et al reviews, showed a significant trend towards increased compliance to therapy favoring the fixed combination therapy, however these results were largely based on retrospective data (2,3). Furthermore, these systematic reviews were inconclusive regarding Blood Pressure efficacy and incidence of side effects. In a recent nested matched case-control analysis, use of a fixed combination antihypertensive therapy was associated with an approximate 2-fold increased risk of serious adverse events, including hypotension, syncope, and collapse, leading to more hospitalizations, as compared to same components of therapy used as free combination. Occurrence of serious adverse events may impact negatively on compliance, as patients and physicians will be reluctant to resume these medications, which in turn, will have negative implications on long-term BP control and cardiovascular outcomes (4). This study and Samir G. Mallat et al results highlight the need for properly designed randomized controlled trials with head to head comparison of fixed versus free drug combination regimens with regards to Blood Pressure-lowering efficacy and adverse events. Several international guidelines, such as the European guidelines, advocated the use of fixed drug combination whenever possible, to improve adherence to therapy. This recommendation is given a class IIb evidence (Usefulness/efficacy is less well established by evidence/opinion), based on the Gupta et al meta-analysis (3). Guidelines from the American society of Hypertension suggested the use of a fixed drug combination to simplify the treatment regimen (5) On the other hand, the published JNC 8 guidelines suggested the use of either strategy to combine antihypertensive drugs (6). Hence; there is a need for additional high quality evidence, and trials with longer follow-up to better guide clinical practice.

3 (3) Does the application provide adequate evidence of efficacy/effectiveness of the medicine for the proposed use? (a) Briefly summarise the reported benefits (e.g. clinical versus surrogate) and comment, where possible, on the actual magnitude of benefit associated with use of the medicine: There is paucity of clinical data on well-designed randomized clinical trial comparing the efficacious combination therapy of lisinopril + hydrochlorothiazide 12.5mg versus a free drug combination, with respect to blood pressure control and incidence of adverse events, in the management of hypertension, however, most of clinical studies included in application were small sized sample with short duration treatment follow up. These studies compared lisinopril 10mg, 20mg + hydrochlorothiazide 12.5mg vs. placebo, demonstrating significant BP reduction, lisinopril + hydrochlorothiazide 12.5mg vs. monotherapy also showed reduction of Blood Pressure and lisinopril + hydrochlorothiazide 12.5mg vs. other dual combination therapies there were no incremental efficacious advantage compare to other fixed dose combination. (b) Is there evidence of efficacy in diverse settings and/or populations? Please provide brief details: Despite of lack of high quality evidence of a fixed combination versus free combination lisinopril + hydrochlorothiazide, Sherrill et al and Gupta et al reviews, showed a significant trend towards increased compliance to therapy favoring the fixed combination therapy, and nonsignificant trends in Blood Pressure control and adverse events favoring the use of a fixed combination based on this, in fact, several international guidelines, such as the European guidelines, advocated the use of fixed drug combination whenever possible, to improve adherence to therapy. This recommendation is given a class IIb evidence (Usefulness/efficacy is less well established by evidence/opinion) (4) Has the application adequately considered the safety and adverse effects of the medicine? Are there any adverse effects of concern, or that may require special monitoring? For more than 27 years now fixed dose combination and free/separate two drugs combination of lisinopril and hydrochlorothiazide have been in use, safety data of both combination therapy in millions of patients has been reported in non-randomized clinical trials, the incidence of adverse events and tolerability did not differ significantly with comparator group. Hydrochlorothiazide dose related adverse effects or toxicity 25mg lowered serum potassium significantly more compared to hydrochlorothiazide 12.5 mg/day by (95% CI to ) mmol/l based on four trials in 642 patients, however, no significant differences were observed between other direct dose comparisons and there was nonsignificant statistical

4 difference on dose related blood pressure lowering effects between hydrochlorothiazide 12.5 mg/day and 25mg/day (6). The proposed formulation fixed dose lisinopril 20 + hydrochlorothiazide 25mg the risk of hypokalaemia outweighs the benefit of lowering blood pressure compare to other proposed formulation with hydrochlorothiazide 12.5mg (5) Please comment on the overall benefit to risk ratio of the medicine (e.g., favourable, uncertain etc). Most patients with hypertension require more than one drug to achieve Blood Pressure target, and monotherapy would only be sufficient in about 20 30% of patients, around 24% to 32% of patients will require a combination of more than two drugs to achieve BP targets. This finding supported by published SPRINT trial, which demonstrated a mean number of Blood Pressure medications of 2.8 was required to achieve a mean systolic Blood Pressure of 121.5mmHg in the intensive treatment group, which resulted in a 25% lower relative risk of cardiovascular events as compared to the standard-treatment group, and in a recent metaanalysis, a target systolic BP of less than 130 mmhg significantly decreased the incidence of cardiovascular events. Despite the lack of high quality evidence, available low-medium quality evidence showed a significant trend towards increased compliance to therapy favoring the fixed combination therapy, and nonsignificant trends in Blood Pressure control and adverse events favoring the use of a fixed combination. Increased compliance may translate into achieving target blood pressure and overall benefit of decreasing cardiovascular events.

5 ADDITIONAL CONSIDERATIONS: (6) Are there special requirements or training needed for the safe, effective and/or appropriate use of the medicine? However, precaution might be considered for the fixed lisinopril + hydrochlorothiazide initiation for the treatment of essential hypertension in patients for whom combination therapy is appropriate, specifically failure to achieve BP goal on monotherapy, should be initiated as free/separate two drugs combination titrated and stabilized at acceptable dose, before switching to the Fixed Dose Combination same dose. (7) Are there any issues regarding the registration of the medicine by regulatory authorities? (e.g., recent registration, new indications, off-label use) For more than 27 years now fixed dose combination and free/separate two drugs combination of lisinopril and hydrochlorothiazide have been in use and registered in several national regulatory authorities. (8) Is the medicine recommended for use in a current WHO GRC-approved Guideline (i.e., post 2008)? Also, several international guidelines, such as the European guidelines, advocated the use of fixed drug combination whenever possible, to improve adherence to therapy. This recommendation is given a class IIb evidence (Usefulness/efficacy is less well established by evidence/opinion), Guidelines from the American society of Hypertension suggested the use of a fixed drug combination to simplify the treatment regimen. On the other hand, the published JNC 8 guidelines suggested the use of either strategy to combine antihypertensive drugs (9) Please comment briefly on issues regarding cost and affordability of this medicine. For more than 20 years now fixed dose combination and free/separate two drugs combination of lisinopril and hydrochlorothiazide have been in use, worldwide available cost effective and affordable in most low-middle income countries. (10) Any additional comments?

6 (11) Please frame the decisions and recommendations that the Expert Committee could make. Despite the lack of high quality evidence, available low-medium quality evidence showed a significant trend towards increased compliance to therapy favoring the fixed combination therapy, and nonsignificant trends in Blood Pressure control and adverse events favoring the use of a fixed combination. Increased compliance may translate into achieving target blood pressure and overall benefit of decreasing cardiovascular events, based on this fact several international guidelines, such as the European guidelines, advocated the use of fixed drug combination whenever possible, to improve adherence to therapy. This recommendation is given a class IIb evidence (Usefulness/efficacy is less well established by evidence/opinion), Guidelines from the American society of Hypertension suggested the use of a fixed drug combination to simplify the treatment regimen. On the other hand, the published JNC 8 guidelines suggested the use of either strategy to combine antihypertensive drugs I recommend inclusion of the following proposed strengths and formulations for inclusion EML, lisinopril 10mg + hydrochlorothiazide12.5mg and lisinopril 20mg + hydrochlorothiazide hctz 12.5mg and NOT lisinopril 20 + hydrochlorothiazide 25mg due safety concern of hypokalaemia on hydrochlorothiazide 25mg dose. The other alternatives to lisinopril + hydrochlorothiazide including; benazepril + hydrochlorothiazide, captopril + hydrochlorothiazide, enalapril + hydrochlorothiazide, fosinopril + hydrochlorothiazide, maxiprep + hydrochlorothiazide, quinapril + hydrochlorothiazide, perindopril + indapamide, shouldn t be included in EML more additional high quality evidence, from randomized clinical trials are needed with longer follow-up, better guide clinical practice. (12) References (if required) 1. Samir G. Mallat,1 Bassem Y. Tanios, Houssam S. Itani, Tamara Lotfi, and Elie A. Ak, Robert K Hills, Free versus Fixed Combination Antihypertensive Therapy for Essential Arterial Hypertension: A Systematic Review and Meta-Analysis, PLoS One. 2016; 11(8): e Published online 2016 Aug 22. doi: /journal.pone Sherrill B, Halpern M, Khan S, Zhang J, Panjabi S. Single-pill vs free-equivalent combination therapies for hypertension: a meta-analysis of health care costs and

7 adherence. Journal of clinical hypertension (Greenwich, Conn). 2011; 13(12): Epub 2011/12/07. doi: /j x PMID: Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010; 55(2): Epub 2009/12/23. doi: /hypertensionaha PMID: wak E, Happe A, Bouget J, Paillard F, Vigneau C, Scarabin PY, et al. Safety of Fixed Dose of Antihy- pertensive Drug Combinations Compared to (Single Pill) Free- Combinations: A Nested Matched Case- Control Analysis. Medicine. 2015; 94(49): e2229. Epub 2015/12/15. doi: /md PMID: Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical practice guide- lines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. Journal of clinical hypertension (Green- wich, Conn). 2014; 16(1): Epub 2013/12/18. doi: /jch PMID: James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). Jama. 2014; 311(5): Epub2013/12/20. doi: /jama PMID: Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database of Systematic Reviews 2014, Issue 5. Art..: CD DOI: / CD pub2.

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