Medical management and monitoring of the hyperthyroid cat: a survey of UK general practitioners

Abstract

Feline hyperthyroidism is commonly diagnosed in general practice. This study assessed the opinions and experiences of UK general practitioners (GPs) regarding the management of feline hyperthyroidism. This included an evaluation of preferred treatment modalities and the monitoring of medically treated cats in relation to thyroxine (T4) level, co-morbid disease and adverse drug reactions. Six hundred and three GPs completed an online questionnaire comprising 34 questions. Oral medication was the most commonly preferred treatment option (65.7% of respondents), followed by thyroidectomy (27.5%) and then radioiodine (5.5%). When cost of treatment was eliminated as a consideration factor, significantly more respondents selected radioiodine (40.5%, P <0.001). Concerning target total T4 levels during medical management, 48.4% aimed for the lower half of the reference interval (RI), 32.3% anywhere within RI, 13.1% within the top half of RI and 0.5% above the RI; 3.4% evaluated efficacy by physical assessment only. In the presence of chronic kidney disease (CKD) respondents were significantly more likely to target total T4 levels within the upper half of the RI (40.3%) or above it (9.8%) when compared with targets for routine cases (P <0.001). Assessment for unmasking of CKD after initiating treatment or for hypertension was not consistently performed. Variability in monitoring strategies may result in CKD and hypertension remaining undetected, inadequate suppression of T4 levels in cats with concurrent CKD and delayed recognition of potentially significant haematological abnormalities.

Introduction

Feline hyperthyroidism was first reported in 1979 and, since that time, has increased in prevalence to become one of the most commonly diagnosed endocrinopathies. ¹ The diagnosis of hyperthyroidism is routinely made in general practice, with at least 91% of cases being confirmed on the basis of elevated total thyroxine (T4) levels. ² There are currently four treatment modalities available, including anti-thyroid medications, surgical thyroidectomy, radioiodine therapy and, more recently, iodine-restricted dietary therapy.^3,4 Choice of treatment modality is believed to be strongly influenced by the individual general practitioner (GP) and is likely influenced by their experience, prior education and awareness of current literature, and specialist opinion.

Treatment options for hyperthyroidism can be separated into those that are potentially curative (radioiodine, surgical thyroidectomy) and those that require life-long intervention and monitoring (anti-thyroid medication, iodine-restricted diet). Most cats will receive anti-thyroid medication at some stage, either for short-term stabilisation before thyroidectomy or radioiodine, or for long-term therapy. Currently, there are two licensed forms of oral anti-thyroid medication available in the UK (methimazole [Felimazole; Dechra Veterinary Products]and sustained release carbimazole [Vidalta; MSD Animal Health]). A transdermal methimazole formulation (unlicensed) became available in August 2012, around the time of data collection for this study.

Co-morbid disease is common in hyperthyroid cats; chronic kidney disease (CKD) can be masked owing to the increase in glomerular filtration rate (GFR) associated with hyperthyroidism and azotaemia may only become evident once the cat becomes euthyroid. ⁵ Additionally, while hypertension has been identified in 22% of newly diagnosed hyperthyroid cats before treatment is initiated, 22–24% of previously normotensive cats develop hypertension following treatment for hyperthyroidism.^6,7

Despite the widespread use of anti-thyroid medications there is a lack of consensus regarding the best practice for monitoring the response to treatment, identification and impact of co-morbid diseases (eg, cardiac disease, renal disease and hypertension), or monitoring for adverse effects of medications. Datasheet guidelines for the licensed medications (NOAH Compendium, www.noahcompendium.co.uk ) provide some guidance; however, descriptive guidance for target serum total T4, the monitoring of blood pressure and co-morbid diseases, such as CKD, is lacking.

Although there is research in this area, the literature is commonly based on referral hospital populations and may not represent the views and experiences of veterinary GPs, who are responsible for the management of most hyperthyroid cats. Previous studies have evaluated the opinions of owners of hyperthyroid cats; however, to our knowledge, there have been no studies evaluating the opinions and decision-making process of GPs regarding choice of treatment modality or their approach to the use of oral anti-thyroid medications.^8,9

This study aimed to evaluate how UK GPs approach management of feline hyperthyroidism. We first hypothesised that GPs would favour oral medication to manage hyperthyroidism over surgery or radioiodine therapy; secondly, that monitoring of kidney function and blood pressure is not routinely practised during therapy; and, thirdly, that the monitoring for adverse effects of medication lacks a consistent approach.

Materials and methods

Target respondents and questionnaire distribution

The Royal College of Veterinary Surgeons register was searched for all UK practices that see feline patients; 2431 practices were identified. Contact was directed to ‘main site’ practices where branch surgeries existed. An email address was available for 1960 practices, while 471 had only registered a postal address. An invitation to complete the questionnaire was distributed via email where available, the remainder was sent by post. Postal contact included a covering letter containing information about the questionnaire with a web address, in order to direct respondents to the online questionnaire.

Most email contact details were generic for public contact to the practice, for example, enquiries@examplepractice.co.uk, and therefore the invitation also contained a request for this to be forwarded to at least one of the practice’s veterinary surgeons. Letters were also published in the UK veterinary press ¹⁰ and online veterinary forums (International Society of Feline Medicine and www.vetsurgeon.co.uk) inviting GPs to take part. Reminder emails were sent 1, 3 and 5 weeks after the questionnaire launch; reminders were not sent to postal recipients owing to cost limitations. The questionnaire was open for completion from 21 August 2012 to 6 October 2012. All responses were anonymous, although respondents who completed the questionnaire could enter a prize draw as an incentive to encourage questionnaire completion.

Questionnaire design

The questionnaire was hosted online using the University of Bristol Online Survey Program. The questionnaire took approximately 15 mins to complete and comprised 34 questions, split into five sections: general information regarding approach to management of hyperthyroidism, oral medical management, surgical treatment (thyroidectomy), the use of iodine-restricted dietary therapy and respondent demographic information. Only responses to questions pertaining to approach to management and oral medical management are reported here; remaining responses are reported elsewhere. ¹¹ A pilot questionnaire of 15 veterinary surgeons was performed to test the design, access and function of the online questionnaire. Following this pilot study a small number of questions were modified for functionality reasons. Most questions were of a ‘closed’ format, with a few ‘open questions’ included where respondents could enter free text. A copy of the questionnaire and postal letter are available from the corresponding author.

Statistical analysis

Categorical responses were summarised using descriptive statistics (percentages only). The association that the categorical variables of perceived cost and the presence of CKD had upon the management strategies of the respondents was assessed by χ² tests. P values <0.05 were considered statistically significant. Statistical analysis was performed using the SPSS 19.0 Statistics program for Windows.

Results

Six hundred and three questionnaires were completed. The majority of respondents were female (n = 345; 57.2%). The year of graduation of the respondents ranged from 1960 to 2012 (median 1996); 78 (12.9%) graduated outside of the UK and Ireland. The median estimated percentage of the working day spent with feline patients was 40% (range 0.25–100%).

In the 6 months leading up to the questionnaire the number of new cases of hyperthyroidism that had been diagnosed was between one and five for 215 respondents (35.7%), six and 10 for 213 (35.3%), 11 and 20 for 140 (23.2%), more than 20 for 28 (4.6%) and zero for seven (1.1%).

Considering respondents’ personal preference for long-term management of hyperthyroidism, 396 (65.7%) chose oral anti-thyroid medication, 166 (27.5%) chose thyroidectomy and 33 (5.5%) chose radioiodine. Eight (1.3%) were either unsure or chose other options, including homoeopathy. As the data were collected shortly after the launch of the iodine-restricted diet, respondents were asked to give the answer that reflected their preference in the time before the diet launch. When cost of treatment was eliminated as a consideration factor, significantly more respondents selected radioiodine (244, 40.5%), with 202 (33.4%) choosing oral medication and 151 (25.0%) selecting thyroidectomy as their preferred management option (P <0.001). Respondents were asked whether they agreed with the statement ‘radioiodine is the gold standard treatment for hyperthyroidism’; 58.9% agreed or strongly agreed, 19.4% disagreed or strongly disagreed, and 21.7% were not sure.

Respondents were asked to rate the importance of factors that might influence their choice of treatment for long-term management of hyperthyroidism in a cat. More than 95% of respondents rated owner compliance with medication, ease of drug administration and the presence of co-morbid disease as very important or important factors in formulating a management plan. Table 1 summarises how respondents rated all factors.

Table 1.

Importance of factors in the formulation of a long-term plan for management of hyperthyroidism in a cat, as rated by 603 UK general practitioners in an online questionnaire (2012)

Factor	Very important /important (number of respondents [% of total respondents])	Not at all/not very important (number of respondents [% of total respondents])	Not sure (number of respondents [% of total respondents])
Owner compliance with medication	591 (98.0)	6 (1)	6 (1)
Ease of drug administration	589 (97.7)	8 (1.3)	6 (1)
Co-morbid disease	582 (96.5)	14 (2.3)	7 (1.2)
Cost of treatment	488 (80.9)	59 (9.8)	56 (9.3)
Cost of monitoring	474 (78.6)	75 (12.4)	54 (9.0)
Risk of surgical complications	460 (76.3)	97 (16.1)	46 (7.6)
Age	402 (66.7)	174 (28.9)	27 (4.5)
Risk of drug side effects	394 (65.3)	135 (22.4)	74 (12.3)
Ease of referral for radioiodine	290 (48.1)	227 (37.6)	86 (14.3)
Whether pet is insured	184 (30.5)	309 (51.2)	110 (18.2)
Indoor vs outdoor cat	119 (19.7)	394 (65.3)	90 (14.9)

When asked which oral anti-thyroid medications they preferred to use in a newly diagnosed hyperthyroid cat, sustained-release carbimazole was favoured by 311 of the respondents (51.6%), methimazole by 244 (40.5%) and 39 (6.5%) had no specific preference. The unlicensed, human form of carbimazole (Neomercazole; Roche Products) was chosen by 9 (1.5%) respondents.

Regarding the monitoring of hyperthyroid cats during management with anti-thyroid medication, 228 (37.8%) respondents stated that they followed a practice protocol (of which 204 were happy with the protocol), 224 (37.1%) designed their monitoring protocols based upon owner preferences and 137 (22.7%) based their monitoring protocols on published medication datasheet advice. Fourteen (2.3%) of the respondents believed that a physical examination was the only necessary monitoring.

Respondents were asked the following question: ‘You have recently diagnosed hyperthyroidism in a 12-year-old cat and prescribed anti-thyroid tablets. Which of the following parameters would you routinely use to monitor the patient and how often?’. A summary of the frequency that parameters were routinely used to monitor patients is provided in Table 2. Of all the possible monitoring parameters body weight, total T4 and renal biochemistry were the most commonly assessed by respondents. Regarding the frequency of monitoring parameters once the cat was stabilised, body weight was the most commonly chosen parameter with 321 (53.2%) respondents monitoring this every 3 months, 220 (36.5%) every 6 months and seven (1.2%) annually. Assessment of total T4 would be routinely monitored every 3 months by 155 (25.7%) respondents, every 6 months by 310 (51.4%) respondents and annually by 45 (7.5%).

Table 2.

Frequency of measurement of monitoring parameters in a recently diagnosed hyperthyroid cat as stated by 603 UK general practitioners in an online questionnaire (2012)

Parameter	Monitoring performed in the first 3–4 weeks and in months 2–6 of treatment (number of respondents [overall %])		Frequency of monitoring once stabilised (number of respondents [overall %])
	3–4 weeks	2–6 months	Every 3 months	Every 6 months	Annually	Not specified
Body weight	529	302	321	220	7	55
	(87.7)	(50.1)	(53.2)	(36.5)	(1.2)	(9.1)
Serum total T4	521	283	155	310	45	93
	(86.4)	(46.9)	(25.7)	(51.4)	(7.5)	(15.4)
Renal biochemistry*	430	192	90	245	117	151
	(71.3)	(31.8)	(14.9)	(40.6)	(19.4)	(25.0)
Hepatic biochemistry †	348	130	60	169	128	246
	(57.7)	(21.6)	(10.0)	(28.0)	(21.2)	(40.8)
PCV	247	87	46	122	106	329
	(41.0)	(14.4)	(7.6)	(20.2)	(17.6)	(54.6)
Complete blood count	285	88	38	129	129	307
	(47.3)	(14.6)	(6.3)	(21.4)	(21.4)	(50.9)
Blood pressure	251	109	91	144	72	296
	(41.6)	(18.1)	(15.1)	(23.9)	(11.9)	(49.1)
Urinalysis (in-house)	231	76	53	124	70	356
	(38.3)	(12.6)	(8.8)	(20.6)	(11.6)	(59.0)
Urinalysis (external)	52	23	4	35	72	492
	(8.6)	(3.8)	(0.7)	(5.8)	(11.9)	(81.6)

PCV = packed cell volume

^*Renal biochemistry was stated as urea, creatinine and phosphate

^†Hepatic biochemistry was stated as alanine aminotransferase and alkaline phosphatase

When asked ‘What level of T4 do you aim for during therapy?’, 292 (48.4%) respondents reported targeting the bottom half of the reference interval (RI), 195 (32.3%) aimed for total T4 to be anywhere within the RI, 79 (13.1%) aimed for the top half of the RI, 11 (1.8%) aimed for total T4 to be below the RI and three (0.5%) above the RI. Twenty-three (3.8%) respondents stated that they did not believe measurement of total T4 was necessary if the cat was clinically stable.

Respondents were then asked how the presence of CKD affected their target total T4. Two hundred and fifty-three (42%) targeted the top half of the RI, 126 (20.9%) stated that they aimed for the bottom half, 100 (16.6%) aimed for the cat not to be hypothyroid, 59 (9.8%) aimed for the total T4 to be above the RI, 46 (7.6%) aimed anywhere in the RI, three (0.5%) aimed below the RI, seven (1.1%) stated that they did not monitor for kidney disease in hyperthyroid cats and nine (1.5%) would still not measure total T4 is if the cat was clinically stable. When comparing these responses to the previous question, respondents were more likely to target total T4 levels within the upper half or above the RI in the presence of CKD (P <0.001).

Four hundred and four (67.0%) respondents indicated that they had seen an adverse reaction to anti-thyroid medication in the previous 12 months. Of these respondents, 185 (49.6%) stated that they had never reported an adverse reaction to anti-thyroid medication to the Veterinary Medicines Directorate, 136 (36.5%) had reported up to 25% of observed reactions, 30 had reported 26–99% and only 22 (5.9%) had reported 100% of the adverse reactions they had seen.

The 404 respondents who stated that they had seen an adverse reaction in the previous 12 months were asked to identify which adverse reactions they had seen. Adverse reactions that had been seen are summarised in Table 3.

Table 3.

Adverse reactions to anti-thyroid medications seen by 404/603 UK general practitioners within the 12 months prior to the completion of an online questionnaire (2012)

Adverse drug reaction seen in the last 12 month period	Number of respondents	Percentage of all respondents experiencing adverse drug reactions (n = 404)
Vomiting	279	69.0
Anorexia	190	47.0
Facial pruritus	181	44.8
Azotaemia	92	22.7
Anaemia	48	11.8
Leukopenia	44	10.9
Hepatic damage	39	9.6
Neutropenia	34	8.4
Thrombocytopenia	34	8.4
Lymphadenomegaly	19	4.7
Death (sudden)	4	0.9

Discussion

Hyperthyroidism is the most frequently diagnosed endocrinopathy in cats and is commonly diagnosed in general practice. ¹ There is limited information regarding the standard approach used by UK GPs in managing and monitoring this disease. This study demonstrates that there is a strong overall preference for the use of oral anti-thyroid medications among UK GPs for the long-term management of feline hyperthyroidism; reasons for specific brand preferences were not investigated. When cost was eliminated from the decision-making process, significantly more respondents chose radioiodine as their treatment of choice (40.0% vs 5.5%). Over 75% of respondents stated that the cost of treatment and the cost of monitoring were important or very important factors in the choice of treatment modality.

The effect of cost for cat owners may be less significant than practitioners believe; 51.3% of owners of hyperthyroid cats surveyed in one study stated that cost had no impact on their decision over which treatment to choose. ⁹ A second survey of owners reported that only 12.1% of owners of hyperthyroid cats were using oral medication because they were concerned about the cost of the other available modalities. ⁸ These studies also identified that a considerable proportion of owners of hyperthyroid cats were not offered radioiodine as a treatment option (53.3%, ⁹ 29.7% ⁸ ). This poses the question of whether UK GPs are more concerned regarding the effect of treatment costs than the owners of their hyperthyroid patients. This may inadvertently lead to reduced numbers of owners being offered referral for radioiodine despite a high proportion of respondents (58.9%) considering it to be the gold standard treatment option. The cost discrepancy between treatment modalities may be even less significant if the long-term cost of treatment and monitoring of patients receiving oral anti-thyroid medications is compared to a one-off sum for radioiodine or thyroidectomy. The longer-term costs may be equivalent, particularly if hyperthyroidism is diagnosed earlier in the disease process, requiring the patient to be medically treated for many years.^12,13

Regarding the monitoring of cats receiving medical treatment for hyperthyroidism, this questionnaire demonstrated that there is a wide variety of approaches. Fourteen respondents stated that they did not monitor cats receiving oral anti-thyroid medications beyond performing a physical examination. Without additional monitoring it would impossible to optimise treatment or identify potentially life-threatening adverse reactions or unmasking of co-morbid conditions such as CKD or hypertension until overt clinical signs developed. Datasheet guidelines formed the basis for the monitoring protocols for 22.7% of respondents. The datasheets (NOAH Compendium, www.noahcompendium.co.uk ) indicate that ‘haematology, biochemistry and serum total T4 should be assessed before initiating treatment and after 3 weeks, 6 weeks, 10 weeks, 20 weeks, and thereafter every 3 months’ (methimazole [Felimazole; Dechra Veterinary Products]) and ‘monitoring of total T4, full haematology and liver and kidney parameters is advised at each recommended follow up visit…3, 5 and 8 weeks after initiation of treatment….and follow-up visits every 3 to 6 months are recommended’ (sustained release carbimazole [Vidalta; MSD Animal Health]). The second datasheet specifies aiming for a total T4 in the bottom half of the RI.

Considering target total T4, 48.4% of respondents in this questionnaire specifically aimed for the bottom half of the RI and only a small proportion (13.1%) aimed for the top half. It is commonly recommended that the total T4 of hyperthyroid cats should be maintained in the lower half of the RI when using medical therapy;^2,12–16 however, there is no current evidence that maintaining a total T4 in the upper half of the RI affects survival. It is possible, however, that if total T4 levels are maintained in the upper end of the RI, the cat may remain mildly hyperthyroid if there is co-morbid disease suppressing total T4 levels or if there is significant fluctuation of total T4 levels.^16,17

Renal biochemistry (urea, creatinine and phosphate) was assessed by the majority of respondents both in the early and maintenance stages of treatment, although 28.7% of respondents did not measure renal parameters routinely after initiating treatment. It has been documented that 15–51% of cats may develop azotaemia following treatment.^18–21 The results of this questionnaire suggest that some practitioners may be overlooking the unmasking of azotaemia following initiation of treatment and, subsequently, the opportunity to instigate appropriate treatment for CKD, which could extend survival. ²²

In the presence of CKD, a statistically significant number of respondents changed their target total T4 to the upper half of the RI or even just above the RI. Previous publications have implied that the development of azotaemia following treatment for hyperthyroidism is an unwanted adverse effect of euthyroidism;^{12,19,23–26} indeed, it is listed under the adverse effects sections of one of the datasheets (sustained release carbimazole [Vidalta; MSD Animal Health]). This is now understood to represent an unmasking of co-existing kidney disease by restoration of GFR.^12,19,24 Adams et al ²⁰ demonstrated a reduction in GFR following treatment for hyperthyroidism; however, the degree of change in GFR did not affect the outcome. More recent studies have also found that the prognosis for survival in cats developing azotaemia after treatment is unaffected unless the cat becomes iatrogenically hypothyroid.^14,21 Conversely, persistent hyperthyroidism maybe detrimental to renal function by inappropriate activation of the renin–angiotensin–aldosterone system (RAAS).^5,7,23 While this increases GFR, the activation of RAAS and secondary systemic and renal afferent arterial hypertension may contribute to the progression or development of CKD and progressive cardiac remodelling, ultimately increasing morbidity and decreasing survival. These recent studies suggest that the concept of maintaining an azotaemic cat in a mildly hyperthyroid state to promote GFR and kidney function is outdated, although the results of this questionnaire suggest that this dogma is still followed by some practitioners.

Only 50.9% of our respondents indicated that they routinely (at least annually) measured blood pressure as part of their monitoring protocol for feline hyperthyroidism. Fourteen to 22% of hyperthyroid cats are reported to be hypertensive at diagnosis and a further 24% are described to develop hypertension de novo following the treatment for hyperthyroidism.^6,7 The low number of practitioners monitoring blood pressure may reflect limited access to blood pressure monitoring equipment or could be because blood pressure monitoring is not advised on the datasheet for either licensed medication. From the questionnaire data we postulate that a considerable proportion of hypertensive cats may be undiagnosed before or after treatment. This may contribute to morbidity with progression of cardiac remodelling and CKD, and potentially may lead to development of ocular and central nervous system complications.^27–29 Furthermore, hypertension has also been shown to be a negative predictor of survival in hyperthyroid cats. ²¹

Adverse reactions were suspected by 67% of respondents in the 12 months leading up to completing the questionnaire, although data were not collected on the frequency of each type of adverse reaction. However, the data suggest that adverse reactions remain common, in particular vomiting and anorexia. This supports previous studies in which gastrointestinal problems were the most frequently reported adverse effects.^30,31

Less than half of the respondents (47.3%) stated that they routinely measure a complete blood count in the early stages of management despite datasheet guidelines. It is not possible to know whether the haematological abnormalities seen by respondents were diagnosed on the basis of a routine monitoring test or owing to the cat presenting with signs of illness. Haematological changes have been reported to occur in 16% of cases, most of which are mild and clinically insignificant; however, some are severe and potentially life-threatening, such as marked thrombocytopenia or neutropenia.^30,31 Monitoring for haematological reactions is most important in the early stages of treatment as these reactions are usually reversible if identified promptly.^31,32 While financial consideration may be a reason for not performing follow-up blood testing, owners should be aware of the requirement to return for reassessment if there is any deterioration in the cat’s condition that could be attributed to an adverse drug reaction.

Only a small proportion of respondents (5.9%) stated that they had reported all the adverse reactions associated with anti-thyroid drugs; nearly half had never reported an adverse reaction. Given the number of respondents who had seen adverse reactions it is likely that the pharmacovigilance data held by the Veterinary Medicines Directorate (VMD) and the pharmaceutical companies will be markedly skewed to suggest a lower frequency. This is possibly owing to cases exhibiting mild adverse reactions to anti-thyroid medications that have been previously reported. Additionally, it may be that practitioners are not reporting adverse reactions if they are ‘expected’. This may have minimal clinical significance; however, if the true frequency of adverse reactions was known it could change the approach to monitoring for some practitioners.

Questionnaire-based studies are prone to bias, intentional or unintentional. We are unable to evaluate the effect of response bias in this study owing to the method of questionnaire distribution. The total number of GPs contacted is not known and therefore a percentage response rate could not be calculated and response bias could not be assessed owing to the anonymity of completed questionnaires. We were also unable to assess whether more than one practitioner completed the questionnaire from each individual veterinary practice.

Questionnaire responses might have been affected by social desirability bias if respondents answered questions by providing what they perceived to be the clinically correct response, rather than the ‘truthful’ answer. ³³ The questions are also unable to account for the real-life variability of individual cases and we acknowledge that the answers to some of the questions would vary dependent upon each case seen; in particular, when asking regarding target total T4 levels in the presence of CKD, we did not specify the International Renal Interest Society stage or stability of CKD.

The true prevalence of adverse reactions could not be determined from the questionnaire as the question format did not evaluate the frequency of reactions per case. We also acknowledge that these responses are reliant on accurate recall by respondents and this may create additional inaccuracy in these data. Finally, the effect of dietary therapy and transdermal methimazole on GPs’ favoured management is unknown; the iodine-restricted diet (Hill’s y/d) had been available for only short period at the time of questionnaire and was not included in general management questions.

Conclusions

There is a preference for the use of anti-thyroid medications in the management of feline hyperthyroidism in UK general practice over potentially curative treatment options. This preference appears to be strongly influenced by cost considerations. Although most GPs do perform some sort of regular monitoring of hyperthyroid cats receiving oral medications, common co-morbid diseases, including hypertension and renal disease, may be undiagnosed and unmanaged in some cases.

Recent information regarding the management of azotaemic cats with hyperthyroidism relating to optimising total T4 levels and detection of hypertension does not appear to be widely implemented in general practice. Azotaemia may still be considered by some practitioners as an adverse reaction to medication or treatment in general rather than evidence that uncontrolled hyperthyroidism may be masking CKD.

Finally, the protocol for monitoring for adverse effects varies significantly between practitioners; however, this study demonstrates that adverse effects may be more common than indicated by data held by the VMD.