Utilisation and Tolerability of Aliskiren in the Primary Care Setting in England

Abstract

Aliskiren (Rasilez), a direct renin inhibitor, is indicated for the treatment of essential hypertension. A postmarketing prescription‐event monitoring (PEM) study was conducted in England to monitor the safety and utilization of aliskiren. Summary statistics and event incidence densities were calculated. The cohort consisted of 6385 individuals with a median age of 68 years (interquartile range, 59–76). Aliskiren was largely prescribed for its licensed indication of hypertension (93.3%) and was reported as “effective” by the prescriber in 77.4% of individuals. Frequently reported clinical events during treatment were diarrhea (3.1% of on‐treatment events), malaise/lassitude (3.0%), and nausea/vomiting (1.2%), which were also common reasons for treatment cessation. Renal events were rare, with 24 cases probably or possibly related to aliskiren use, and four of which were classified as acute renal failure using RIFLE (Risk Injury Failure Loss End‐Stage Kidney Disease) criteria. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies to optimize the safe prescribing of aliskiren.

Aliskiren (Rasilez, Novartis, Basel, Switzerland), a direct inhibitor of the enzyme renin, was launched into the UK market in August 2007. It is indicated for the treatment of essential hypertension and can be used alone or in combination with other medicines for the treatment of hypertension.1 Aliskiren acts on the renin‐angiotensin‐aldosterone system, by preventing the production of angiotensin I and II as well as reducing plasma renin activity.2 Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are further antihypertensive agents that act on the renin‐angiotensin system and are recommended for first‐line treatment in individuals younger than 55 years.3 These agents, however, have been associated with adverse renal events especially in elderly individuals and those with arterial stenosis.4, 5 Furthermore, ACE inhibitors and ARBs have also been associated with angioneurotic edema caused by the reduction in bradykinin breakdown and consequent vasodilatation.6, 7, 8 Since aliskiren also acts on the renin‐angiotensin system, renal and angioneurotic edema events were a potential concern for aliskiren. Premarketing studies of aliskiren found the drug to be well tolerated with a side‐effect profile similar to placebo.9, 10

Approximately 1 billion people worldwide have hypertension, which is defined as a persistent raised blood pressure (BP) >140/90 mm Hg.11 Control of BP in patients with hypertension is commonly achieved via the use of a combination of antihypertensive agents.12 Hypertension is classed as either essential (primary) hypertension, with unknown underlying causes, or as secondary hypertension, commonly a result of renal or endocrine disease.13 Hypertension is a major risk factor for stroke, myocardial infarction, congestive heart failure, and renal disease.14 Multiple antihypertensive agents are often required in order to successfully control high BP, with as many as 47.7% of individuals using more than a single agent.15

To complement safety knowledge from other sources, including spontaneous reporting systems and clinical studies, the Drug Safety Research Unit (DSRU) carried out a postmarketing surveillance study of aliskiren using the observational cohort technique of prescription‐event monitoring (PEM).16 The aim of this observational study was to monitor the safety and utilization of aliskiren prescribed in the primary care setting in England by general practitioners (GPs). PEM is conducted in accordance with international ethical guidelines.17

Methods

Prescription Event Monitoring

Exposure data were obtained from dispensed National Health Service (NHS) prescriptions for aliskiren, issued by GPs in England between February 2008 and November 2010. These prescriptions were collated by the NHS Business Services Authority Prescription Services (NHSBSA). GPs were sent questionnaires at least 6 months after the date of the patient's first prescription for aliskiren. The questionnaires collected data on patient demographics, prescribing indication, prescribing dose, duration of treatment, reason for stopping treatment (where treatment had stopped), and information regarding events experienced by the patient both on and off treatment. An additional question on chronic kidney disease (CKD) was included within the questionnaire for this study since CKD was a potential risk factor for renal events with the use of aliskiren.

An event was coded as an adverse drug reaction (ADR) if the GP specified that a reported event was attributable to aliskiren. All events reported on the questionnaires were coded onto the PEM database using the DSRU Event Dictionary. In this hierarchical dictionary, doctor summary event terms (terminology used by the reporting physician) are grouped under lower‐level event terms, which are linked to broader higher‐level event terms and finally to a system‐organ class (SOC).

Furthermore, rare and iatrogenic serious adverse events (RAIDAR), often related to drug exposure, were followed up if an alternative explanation for their occurrence was not given. RAIDAR included angioneurotic edema and acute renal failure, which were of particular interest with aliskiren. Other renal events were also followed up given that renal dysfunction was a known risk with aliskiren. Pregnancies were followed up to ascertain outcome. Deaths were also followed up if no clear cause of death could be established from the questionnaire.

Individual case reports were assessed independently for drug‐relatedness by two research fellows (at least one medically qualified) in order to ascertain the likelihood of an event being related to aliskiren. In the case of disagreement between research fellows, arbitration by a third research fellow was undertaken. Drug‐relatedness assessment involved the classification of case reports into four graded categories: probable, possible, unlikely, or unassessable. Criteria for classification were temporality, pharmacologic plausibility, concomitant treatment, re‐/de‐challenge, medical history, and the exclusion of other causes.¹,18 Events were reported as common (>1% but <10%), uncommon (>0.1% but <1%), and rare (>0.01% but <0.1%).

Sample Size

A sample size of 10,000 patients is desirable for PEM studies.16 However, a final cohort of 6385 patients was achieved. A sample size of at least 5000 should allow for the detection of at least three cases of an ADR with 85% power if the reaction occurs at a frequency of at least one in 1000 patients and assuming the background rate is zero.

Statistical Analysis

Summary statistics were calculated for the demographic and drug utilization characteristics of patients within the final evaluable cohort and are shown in Table 2.

Table 2.

Characteristics of the Final Cohort

Characteristics	No. (% of Total Cohort) N=6385
Age, yearsa
0–9	2 (0.0)
10–19	3 (0.1)
20–29	23 (0.4)
20–39	122 (1.9)
40–49	495 (7.8)
50–59	995 (15.6)
60–69	1749 (27.4)
70–79	1934 (30.3)
80–89	1000 (15.7)
≥90	62 (1.0)
Median age (IQR)	68 (59–76)
Sex
Male	2821 (44.2)
Female	3557 (55.7)
Not known (% of total)	7 (0.1)
Indication
Hypertension	5958 (93.3)
Chronic renal failure	90 (1.4)
Diabetes mellitus	68 (1.1)
Intolerance to previous drug	48 (0.8)
Proteinuria	42 (0.7)
Other indications	91 (1.4)
Not known (% of total)	289 (4.5)
Preexisting CKD
Yes	2130 (33.4)
No	3976 (62.3)
Not known (% of total)	279 (4.4)
Smoking history
Current smoker	540 (8.5)
Ex‐smoker	2024 (31.7)
Never smoked	3364 (52.7)
Not known (% of total)	457 (7.2)

Abbreviations: CKD, chronic kidney disease; IQR, interquartile range. ^aAt start of treatment.

Incidence densities (IDs) of all first reports of events occurring in patients during treatment with aliskiren were calculated. ID is expressed as the number of reports of an event per 1000 patient‐months of treatment. Patient‐months of exposure are based on patients for whom either the date of stopping aliskiren was known or who continued to take aliskiren until the end of the study period. In order to detect any early‐onset events, the differences between ID in month 1 (ID₁) and months 2 to 6 (ID_2–6) of treatment were calculated with 95% confidence intervals (CIs).

Renal events that were assessed as probably or possibly associated with aliskiren were classified according to RIFLE (Risk Injury Failure Loss End‐Stage Kidney Disease) criteria, based on their renal function at the time of event compared with baseline. The different classes of acute kidney injury (AKI) within the RIFLE classification are presented in Table 1.19 Classification of renal events enables the severity of renal events associated with aliskiren to be determined. The characteristics of the subset of patients with renal events probably or possibly associated with aliskiren were also summarized.

Table 1.

RIFLE (Risk Injury Failure Loss End‐Stage Kidney Disease) Classification19

Class	GFR Criteria	Urine Output Criteria
Risk	Increased SCr 1.5× or decreased GFR >25%	<0.5 mL/kg/h×6 h
Injury	Increased SCr 2× or decreased GFR >50%	<0.5 mL/kg/h×12 h
Failure	Increased SCr 3× (or ≥4 mg/dL) or decreased GFR >75%	<0.3 mL/kg/h×24 h or anuria×12 h
Loss of kidney function	Persistent ARF, ie, complete loss of kidney function >4 weeks
End‐stage kidney disease	Complete loss of kidney function >3 months

Abbreviations: ARF, acute renal failure; GFR, glomerular filtration rate; SCr, serum creatinine.

Results

Study Cohort

A total of 14,874 questionnaires were posted to GPs, of which 7794 (52.4%) were returned to the DSRU. A total of 1409 (18.1%) of the returned forms were classified as void because they did not contain any clinically relevant data. The final cohort comprised 6385 evaluable patients: 44.2% (n=2821) men and 55.7% (n=3557) women. The median age was 68 years (interquartile range [IQR], 59–76 years): 65 years (IQR, 56–73 years) for men and 72 years (IQR, 62–79 years) for women. Summary characteristics of the evaluable cohort are shown in Table 2.

Use of Aliskiren

The most commonly reported primary indication for aliskiren was hypertension in 93.3% (n=5958) of patients. Of these, 99.2% (n=5908) reported essential hypertension. Other reported indications were chronic renal failure (n=90, 1.4%) and diabetes mellitus (n=68, 1.1%). For patients younger than 20 years, indications were essential hypertension (n=2), attention deficit hyperactivity disorder (ADHD, n=1), hypertension and nephrotic syndrome (n=1), and not specified (n=1). The most commonly reported starting dose of aliskiren was 150 mg OD (89.7%, 5389 of 6007) as recommended in the Summary of Product Characteristics (SPC). A higher starting dose of 300 mg OD was reported in 584 (9.7%) patients, which is the recommended dose for uptitration from an initial dose of 150 mg OD. A small number of the patients reported starting doses other than those recommended in the SPC (n=34, 0.6%), the majority of which initiated aliskiren at 75 mg OD (n=29).

Where an opinion on the effectiveness was provided by the prescriber, aliskiren treatment was thought to have been effective in 77.4% (3888 of 5024) of individuals. A total of 34.8% (2202 of 6322) of patients were reported as having stopped using aliskiren during the study period (unspecified stopping status for 63 patients). GPs recorded 2388 reasons for stopping aliskiren therapy in 1829 patients (28.6% of cohort). The most frequent cause for cessation of treatment was “not effective” (n=397, 16.6% of all reasons for stopping). Diarrhea (n=123, 5.2% of all reasons for stopping), intolerance (n=92, 3.9%), unspecified side effects (n=82, 3.4%), dizziness (n=77, 3.2%), and malaise (n=74, 3.1%) were also commonly reported reasons for stopping.

Concomitant use of P‐glycoprotein (P‐GP) inhibitors, such as amiodarone, erythromycin, cyclosporine, verapamil, clarithromycin, erythromycin, telithromycin, or itraconazole, with aliskiren, a contraindication for use of the product, was observed in 368 patients (6.2% of cohort where use of P‐GP inhibitor specified). Furthermore, concurrent use of ACE inhibitors or ARBs with aliskiren was observed in 11 patients with renal events probably or possibly related to aliskiren use (11 of 24, 45.8%). Although these were not contraindications at initial study start date, concomitant use of aliskiren with ACE inhibitors or ARBs in patients with diabetes mellitus or renal impairment (glomerular filtration rate [GFR] <60 mL/min/1.73 m²) was added as a contraindication in the SPC in 2012 (after this study had ended). In addition, aliskiren is also contraindicated for use in patients younger than 18 years; however, three patients (0.1% of cohort) who had been prescribed aliskiren were younger than 18 years. A total of 282 patients (4.4% of the cohort) with preexisting CKD stages IV or V were being prescribed aliskiren. Although use in severe renal impairment was a caution for use at initial study start date, it is now no longer recommended for use in cases of severe renal impairment (GFR <30 mL/min/1.73 m²) within the SPC.

Event Incidence During Treatment With Aliskiren

The most frequently reported events during the first 6 months of aliskiren treatment are shown in Table 3. A total of 6544 events were reported in 2930 patients, and 6104 of these events were reported to have occurred during treatment with aliskiren. Of these events, 1589 (26.0%) occurred within the “general” SOC, including “not effective” (n=404, 6.6%) and “intolerance” (n=96, 1.6%), which were more commonly associated with the first month of treatment vs months 2 to 6. A further event from the general SOC, “dose reduced” (n=30, 0.5%), was associated with months 2 to 6 rather than the first month of treatment with an ID₁–ID_2‐6 of −0.57 (95% CI, −0.87 to −0.27).

Table 3.

IDs for Events During the First 6 Months of Treatment, Ranked in Order of ID₁ for Events Where ID₁ ≥3

DSRU Dictionary Higher Term	N1	N2–6	ID1	ID2–6	ID1–ID2–6 (95% CI)	ADR	RFS
Not effective	109	233	18.91	9.48	9.43 (5.67–13.18)	NA	397
Malaise, lassitude	85	67	14.74	2.73	12.02 (8.82–15.22)	38	129
Diarrhea	78	80	13.53	3.26	10.27 (7.19–13.36)	26	123
Dizziness	63	64	10.93	2.60	8.32 (5.55–11.10)	14	77
Dose increased	56	242	9.71	9.85	−0.13 (−2.96 to 2.70)	NA	2
Patient request to stop aliskiren	50	55	8.67	2.24	6.43 (3.96–8.91)	NA	121
Headache, migraine	49	47	8.50	1.91	6.59 (4.15–9.03)	13	59
No further request by patient for aliskiren	49	50	8.50	2.03	6.46 (4.02–8.91)	NA	111
Intolerance	43	42	7.46	1.71	5.75 (3.46–8.04)	1	92
Unspecified side effects	40	33	6.94	1.34	5.60 (3.40–7.79)	92	82
Hospital referrals no admission	37	77	6.42	3.13	3.28 (1.10–5.47)	NA	53
Hypertension	36	22	6.24	0.90	5.35 (3.28–7.42)	0	9
Nausea, vomiting	35	27	6.07	1.10	4.97 (2.92–7.03)	6	44
Edema	30	52	5.20	2.12	3.09 (1.14–5.04)	16	21
Renal function test abnormal	30	37	5.20	1.51	3.70 (1.77–5.62)	5	59
Non compliance	26	20	4.51	0.81	3.70 (1.93–5.47)	NA	64
Pain abdomen	26	28	4.51	1.14	3.37 (1.59–5.15)	3	27
Electrolyte abnormal	21	40	3.64	1.63	2.01 (0.38–3.65)	4	61
Cough	20	38	3.47	1.55	1.92 (0.32–3.52)	11	29
Upper respiratory tract infection	20	50	3.47	2.03	1.43 (−0.19 to 3.06)	1	7

Abbreviations: ADR, adverse drug reaction; CI, 95% confidence interval for ID₁–ID_2–6; ID₁, incidence density for each event during the first month of treatment; ID_2–6, incidence density for each event during treatment months 2 to 6; ID₁˗ID_2–6, arithmetic difference between ID₁ and ID_2–6; N₁, total number of reports of each event during the first month of treatment; N_2–6, total number of reports of each event during treatment in months 2 to 6; NA, not applicable; RFS, reason for stopping.

Clinical events associated with starting therapy were abnormal results on renal function test (n=94, 1.5%), electrolyte abnormality (n=85, 1.4%), diarrhea (n=190, 3.1%), and dizziness (n=152, 2.5%). Malaise/lassitude (n=182, 3.0%), headache/migraine (n=109, 1.8%), nausea/vomiting (n=72, 1.2%), abdominal pain (n=63, 1.0%), and cough (n=77, 1.3%) were also associated with starting therapy. On the other hand, deafness (n=8, 0.1%, ID₁–ID_2–6=−0.20; 95% CI, −0.38 to −0.03), gastroscopy (n=9, 0.1%, ID₁–ID_2–6=−0.20; 95% CI −0.38 to −0.03), and proteinuria (n=5, 0.1%, ID₁–ID_2–6=−0.20; 95% CI −0.38 to −0.03) were associated with delayed onset (months 2–6).

Clinical events of interest included renal failure (n=31, 0.5%, ID₁–ID_2–6=0.98; 95% CI −0.01 to 1.97), angioneurotic edema (n=5, 0.1%, ID₁–ID_2–6=0.44; 95% CI −0.16 to 1.04), anemia (n=14, 0.2%, ID₁–ID_2–6=−0.19; 95% CI −0.61 to 0.22), joint pain (n=83, 1.4%, ID₁–ID_2–6=0.64; 95% CI −0.74 to 2.02), and rash (n=67, 1.1% of all on‐treatment events, ID₁–ID_2–6=1.27; 95% CI −0.17 to 2.71). A total of 14 patients (0.2% total cohort) reported RAIDAR events during treatment with aliskiren, including angioneurotic edema (n=5), leukopenia (n=2), pancreatitis (n=1), thrombocytopenia (n=3), nephrotic syndrome (n=1), alveolitis fibrosing (n=1), and neutropenia (n=1).

Renal Events

Overall, 183 renal events were reported in 120 patients. This included 143 (78.1%) events of abnormal results on renal function test (including raised urea or creatinine or reduced estimated GFR) as well as 40 (21.9%) events of renal failure. Follow‐up of 65 of the 120 patients with renal events was performed as no alternative cause for the renal event was more likely than aliskiren. Follow‐up enabled drug‐relatedness assessment to be performed in 51 patients. Results of the drug‐related assessments are shown in Table 4. A total of 24 renal events, in 24 patients, were thought to be possibly or probably related to aliskiren use. The classification of these 24 renal events using RIFLE criteria is shown in Table 5. This classification resulted in only four cases of acute renal failure, which were all possibly related to the use of aliskiren. A large proportion of the individuals with renal events were 70 years or older (18 of 24, 75.0%) and had preexisting CKD (19 of 24, 79.2%) or diabetes mellitus (15 of 24, 62.5%), which are all risk factors for AKI. Furthermore, eight individuals with renal events were found to have both diabetes mellitus and concomitant use of ACE inhibitors/ARBs (8 of 24, 33.3%) and eight individuals were also found to have CKD and concomitant use of ACE inhibitors/ARBs (8 of 24, 33.3%). Nine individuals with renal events were taking 150 mg OD (9 of 24, 37.5%), nine were taking 300 mg OD (9 of 24, 37.5%), and six were taking unknown doses (6 of 24, 25.0%). The characteristics of individuals experiencing these renal events are shown in Table 6.

Table 4.

Drug‐Relatedness Assessment of Renal Events

Drug‐Relatedness Assessment	No. (% of Returned Follow‐Up)
Probable	8 (15.7)
Possible	16 (31.4)
Unlikely	13 (25.5)
Unassessable	14 (27.5)
Total	51 (100.0)

Table 5.

RIFLE (Risk Injury Failure Loss End‐Stage Kidney Disease) Classification of Renal Events

RIFLE criteria	Probable	Possible	Total	Percent of Subset	Percent of Cohort
Acute renal failure	0	4	4	16.7	0.1
Renal injury	2	1	3	12.5	0.1
Risk of renal injury	4	7	11	45.8	0.2
Renal function test decline	2	4	6	25.0	0.1
Total	8	16	24	100.0	0.4

Table 6.

Characteristics of Patients With Renal Events Probably or Possibly Related to Aliskiren

Characteristics	No. (%) N=24
Age, years
30–39	1 (4.2)
40–49	1 (4.2)
50–59	2 (8.3)
60–69	2 (8.3)
70–79	10 (41.7)
80–89	7 (29.2)
90–99	1 (4.2)
Aliskerin dose
150 mg OD	9 (37.5)
300 mg OD	9 (37.5)
Not known	6 (25.0)
CKD stage
I	0 (0.0)
II	0 (0.0)
III	13 (54.2)
IV	6 (25.0)
V	0 (0.0)
Diabetes mellitus
Yes	15 (62.5)
No	9 (37.5)
Concurrent ACE inhibitor/ARB
ACE inhibitor	3 (12.5)
ARB	9 (37.5)

Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; OD, once daily.

Pregnancies

There were no pregnancies reported for this final cohort.

Deaths

The number of deaths reported during the study was low (n=100, 1.6% of the final cohort). This included 44 (44.0%) on‐treatment, 47 (47.0%) off‐treatment, and nine (9.0%) with unknown treatment status. The cause of death was established in 76 patients, with the most common cause of death resulting from cardiovascular conditions (n=34, 44.7% of known cause of death).

Discussion

Aliskiren was prescribed for its licensed indication of hypertension in at least 93.3% of patients and was initiated at the recommended starting dose of 150 mg OD. Most patients continued aliskiren throughout the entire study period and the antihypertensive agent was thought to be largely effective as indicated by prescribers in 77.4% of cases. The most commonly reported reason for aliskiren treatment being stopped was that it had not been effective (16.6% of all reasons for stopping).

Overall, diarrhea, which was a common event in both premarketing and postmarketing studies, was the most common reported clinical event in this cohort (n=190, 3.1% of all on‐treatment events) and was associated with the first month of treatment (ID₁–ID_2–6=10.27; 95% CI, 7.19–13.36). In contrast to premarketing studies, however, diarrhea was also a common reason for stopping aliskiren in this study (5.2% of all reasons for stopping). Diarrhea is an adverse event reported in both ACE inhibitors and ARBs; however, the mechanism by which these drugs cause diarrhea remains unclear.20, 21 A noninferiority trial of patients 65 years and older with essential systolic hypertension demonstrated that the incidence of diarrhea was greater in patients taking aliskiren (6.6%) compared with those taking the ACE inhibitor ramipril (5.0%) over 9 months.1

Abnormal results from renal function tests were reported more commonly in this cohort than in premarketing studies and, in contrast to these studies, were a common reason for stopping aliskiren. Abnormal renal function test results were associated with the first month of aliskiren therapy (ID₁–ID_2–6=3.70; 95% CI, 1.77–5.62). Reports of renal failure were uncommon, which is in keeping with premarketing experience, and was also an uncommon reason for stopping aliskiren.

In the subset of renal events assessed to be probably or possibly related to aliskiren, the majority of patients were 70 years and older and had other risk factors for renal events, including CKD and diabetes mellitus. Patients with these risk factors, however, had less severe renal events using the RIFLE criteria. This may be a result of CKD diagnosis encouraging greater surveillance of renal function and protection against progression toward more serious events. The majority of patients with events suggestive of acute renal failure had diabetes mellitus and concomitant use of ACE inhibitors/ARBs. This is consistent with the findings in the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE)22 (a study of aliskiren use and cardiorenal endpoints in patients with type II diabetes mellitus and CKD), where renal impairment occurred in 9.8% of the aliskiren group vs 8.7% in the placebo group in individuals using ACE inhibitors/ARBs. These findings led to an update in 2012 to the aliskiren product information to contraindicate the concomitant use of ACE inhibitors/ARBs with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).23 The Six Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality in Patients With Acute Decompensated Heart Failure (ASTRONAUT) trial24 also found renal impairment or failure to be more common when aliskiren was added to standard therapy vs placebo in hospitalized patients admitted for heart failure (relative risk, 1.37; 95% CI, 1.08–1.75).

Reports of angioneurotic edema and related symptoms and signs were reported more frequently in this study than might be expected from premarketing studies, where this event was rarely reported.1 Higher frequencies have, however, been observed in pooled safety data from 12,942 patients from 13 randomized control trials, which showed angioedema to occur in 0.6% of aliskiren monotherapy users.25 On the other hand, a further systematic analysis of 5141 patients from randomized control trials showed a lower incidence rate of angioedema at 0.13%.26 It is possible that the pooled data from the 12,942 patients may have overestimated the incidence of angioedema by including cases of urticaria.

Deaths were not frequent (1.6% of total cohort) and were most commonly a result of cardiovascular conditions (44.7% of deaths where cause was specified). There were no reported pregnancies within this study.

Further investigation might include the use of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria to identify AKI more accurately, which would enable an improved assessment of renal events.27 This forms the basis of the National Institute for Health and Care Excellence (NICE) guidelines for the prevention, detection, and management of AKI published in the UK in 2013.28 The KDIGO classification also incorporates the application of AKI criteria to patients where the changes from baseline have occurred within 48 hours to 1 week in order to capture acute cases.29

Study Limitations

A limitation to this study was the response rate of GPs to posted questionnaires, which was 52.4%. Nonresponse can lead to nonresponse bias, when the characteristics of patients who attend responding GPs are different than the characteristics of patients who attend nonresponding GPs. However, this level of response is similar to other postal surveys30 and reporting using PEM remains higher than reporting using the Yellow Card Scheme.31, 32 Furthermore, the study was unable to capture prescriptions dispensed within the secondary care setting, such as hospitals. The lack of information concerning secondary care prescription might have led to survivor bias within the study. Channelling bias can also occur with newly marketed medicinal products, as patients who do not respond to other treatments may be prescribed the new drug. In this study, however, only 15 individuals were reported to have been prescribed aliskiren for hypertension that was nonresponsive to other previous treatments. The use of dispensed prescriptions as a measure of drug utilization within this study has its limitations as this method does not account for noncompliance with treatment regimens. The study questionnaire did not specifically request information regarding GP awareness of noncompliance; however, the GP was able to report noncompliance if he/she considered this to be an important event. This limitation should be taken into account when interpreting the incidence of specific events. Finally, reasons for prescribing aliskiren over ACE inhibitors or ARBs could not be ascertained via this study as this information was not specifically requested. However, it is thought that aliskiren may be prescribed in individuals with hypertension uncontrolled by other treatment options or in individuals who are unable to tolerate other treatment options.33

Conclusions

Results from this postmarketing observational study demonstrate that aliskiren is largely being prescribed for its licensed indication and is generally well tolerated. Renal events were common in patients with risk factors for AKI as well as those using ACE inhibitors/ARBs. However, the patients with risk factors for renal disease including preexisting CKD or diabetes mellitus had less severe renal events by RIFLE criteria than individuals without these risk factors. This may have been the result of healthcare professionals more intensively monitoring patients who were at increased risk for renal events, thus preventing progression to AKI. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies in order to optimize the safe prescribing of aliskiren.

Disclosure

The DSRU receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The DSRU has received financial support from Novartis, the manufacturer of Rasilez.

J Clin Hypertens (Greenwich). 2016;18:1237–1243. DOI: 10.1111/jch.12852. © 2016 Wiley Periodicals, Inc.