Warfarin dose adjustment was performed for nontherapeutic INR values (more than 66 % of total INR values). Among these, warfarin dose was decreased in 3.4 % of subtherapeutic INRs and increased in 4.2 % of supratherapeutic INR ranges, although there was no clear reason documented for such paradox. In addition, the dose adjustments of only 13.4 % of nontherapeutic INRs were dependent on the recent INR values and cumulative weekly doses of warfarin, as recommended by ACCP guideline . These imply that, most of anticoagulation management might have done by clinical evaluation of the patients’ conditions. Although this approach have paramount importance, it would be much better if supported by available valid guidelines. Such practices might not allow someone to know the direct effect of changes in medication dose and might result in suboptimal quality of anticoagulation management. This could be demonstrated by the low time patients stay in therapeutic INR range (33.5 %). Hence, the percentage of INRs in therapeutic range highly depends on the quality of dose management .
Among patients for which analysis of the effect of warfarin dose on the value of INR values was performed, nearly 10 % of INR values for which warfarin dosage had been adjusted were in the therapeutic range. The key informants stated that although dosage changes should be done based on the state of INR, patients’ conditions were taken into account. For example, for patients with certain conditions such as peptic ulcer and other conditions of bleeding events, the risk-benefit ratio would be considered and dosage changes might be done accordingly, even if the INR values were within the therapeutic range. According to other studies, dosage change is not recommended for therapeutic INR values , for a single INR that is slightly out of range [9, 10]. ACCP guidelines also do not support dosage change for therapeutic INRs . Therefore, it is important to consider the standard guidelines while deciding to modify/adjust the maintenance anticoagulant doses.
Warfarin weekly dose change ranged between 16 to 100 % for recent subtherapeutic INRs, 16 to 50 % for therapeutic and 11 to 66 % for overtherapeutic INRs. But, according to ACCP guidelines, patients whose INR is just outside the therapeutic range can be managed by either adjusting the dose up or down in increments of 5 to 20 % . Other studies also recommended that dosage changes should be altered by the total weekly dose of 5 to 20 % [8, 9, 11, 12]. Variability in the amount or percentage of warfarin dosage change might be due to the absence of local dosing protocol or failure to adhere to the available international guideline. It is important to adhere to the international standard treatment guidelines where there are no local treatment protocols while deciding to modify/adjust the maintenance anticoagulant dosages for nontherapeutic INR values. Institutional protocols for dosing decisions during maintenance VKA therapy should be developed and used accordingly in order to minimize consequences of DRPs in patients with DVT.
In the present study, change in warfarin dose up or down showed significant linear relationship with consequent INR values (p = 0.000). Accordingly, about 42 % of the variations in INR values were accounted for by warfarin dosage change. As a result, percentage of weekly warfarin dosage reduction (up to 70 %) was related to the consequent nontherapeutic low INR values. Therefore, dose reductions might be one of the reasons for low INRs and dosage changes especially higher dose reductions could be major DRPs that might expose the patients to high risk of recurrent thrombosis complications. As evident from the current finding, more than 12 % were presented with significantly under-therapeutic INR range (INR less than 1.5) at weekly warfarin dose reduction of 21–70 %. This finding is in agreement with reports of different studies that, response to a previous change in warfarin dosage was the cause of under-anticoagulation  and low INR values [10, 14]. Therefore, high dosage changes greater than 20 % are not advisable and should be avoided in order to minimize complications such as recurrent thrombosis. But, there might be exceptions that need special considerations of higher doses including concurrent medications such as amiodarone and rifampin which need a total weekly dose reduction and increment of 50 %, respectively .
Five (12.2 %) patients presented with over-therapeutic INRs at weekly warfarin dosage increment ranging from 11 to 100 %. This might increase the risk of overanticoagulation and thus expose the patients to high risk of bleeding complications as supported by different studies [13, 16]. Dosage increment greater than 20 % should be avoided especially as the dosages become increased more than 40 % the risks might be more. There were 3 cases (7.3 %) in the current study that presented with an INR value greater than 4.0 at greater than 40 % dosage increment. It was not possible to say anything about these patients, as there were no documented adverse events except for some minor undesirable effects (9 %) such as nasal and vaginal bleeding, which were said to be not related to the above factor. But, INR values greater than 3.3 were recorded at the time of these bleeding events although there was no recent dose adjustment done that allows us to correlate with warfarin overdose. Nevertheless, the risk of bleeding should be an issue of utmost importance. Therefore, these trends should be guided by valid treatment guidelines in order to improve clinical outcomes and minimize unwanted complications due to anticoagulant drug overdose.
As the findings of this study showed, there had been potential interactions that could make INR to fall out of the therapeutic range. About 42 % of patients received warfarin concomitantly with 18 other medications that have potentially major or moderate interaction with warfarin. For more than 46 % (19/41) of patients, co-administration was made at the time of dosage adjustment. The fact that about 58 % of patients, in which drug-interaction was a concern, had non-therapeutic INR range suggests that whenever there is a need for dosage changes in patients with DVT the concurrent medications should be considered. It was stated that for most interactions a total weekly dose adjustment of either an increase or decrease of 30 % is needed except for certain drugs such as amiodarone and rifampin which need a total weekly dose reduction and increment of 50 %, respectively . But, in the present study, both dose reductions and increments were done up to 50 % regardless of the type of concurrent medications and this might expose the patients to the risk of recurrent or hemorrhage complications.
Norfloxacin and metronidazole were prescribed for only one and two patients who were on warfarin, respectively. In both cases an increased INR value was showed but no apparent risk of bleeding since the increment was from low to therapeutic INR range. But one study reported that, metronidazole had shown an impact on bleeding risk when used with warfarin concomitantly . In another study, all patients who received quinolone antibiotics concomitantly with warfarin had INR values above 3.5, suggesting drug-induced warfarin potentiation . Rifampin was prescribed for 2 patients. Out of these, one patient’s INR was dropped from 1.31 to 1.27 following warfarin increment of 33 % and the other patient’s INR increased from 1.33 to 2.1 following warfarin increment of 50 %, suggesting major drug-drug interaction and need of large increment of warfarin dose. This is supported by a practice guideline , which stated that for rifampin interactions a cumulative weekly dose of warfarin increment of 50 % is needed. Whenever there is a need of anticoagulant dosage changes in patients with DVT, changes in concurrent medications especially those with major interactions with VKAs should be considered.
Tramadol was reported to increase the risk of bleeding . In the present study, this drug was prescribed for 17 patients who were on warfarin therapy. Among these, INR values of 6 patients were increased to supratherapeutic ranges suggesting tramadol-induced warfarin potentiation but difficult to generalize since warfarin dose increment of 20–50 % was performed during this time. In addition, more than 41 % of tramadol prescriptions were written on a PRN (as required) basis without specified maximum daily doses. This might contribute to unintentional administration of over-dosage (more than 400 mg per day) and might also lead to increased effect of warfarin and its bleeding risk. Thus, it would be helpful to write full dosage schedule including the maximum daily dosage whenever medications are ordered especially when prescribed on the basis of PRN.
Vitamin K is known to reverse warfarin’s pharmacologic activity, and many foods containing sufficient vitamin K reduce the anticoagulation effect of warfarin if a patient consumes them in large portions or repetitively within a short period of time. The present study showed that more than 12 % were instructed to avoid green leafy vegetables (rich in vitamin K) during their anticoagulation treatment. Responses from key informants regarding such practice were taken. Some of them suggested that unexplained changes in INR records might force to consider absolute avoidance of diets rich in vitamin K. This was not in agreement with other report that suggested considering abrupt changes rather than avoidance . In the contrary, other informants said this was not the practice and strongly underlined to a consistent and moderate intake of such foods, as also supported by different studies [20, 21]. One study revealed that changes in dietary vitamin K intake were among the causes of INRs below 2.0 and above 4.0 . Others also recommended that patients should be encouraged to maintain consistency in their vitamin K intake and should strive to meet the recommended dietary allowance for vitamin K [19, 21] because dietary content or extent of absorption of vitamin K might have effect on warfarin . Patients should be given a list of vitamin K rich foods and encouraged to maintain consistency in their vitamin K intake rather than absolute avoidance and alternative sources of vitamin K, such as multivitamins and nutritional supplements should also be considered.
It is difficult to assess actual prevalence of patient non-adherence from medical charts. Regardless of this, some possible causes of non-adherence were documented in 6.6 % of studied population and the most common was missing doses. Although three of four patients with documented non-adherence had a nontherapeutic INR range, the low number of these cases compared to patients without non-adherence did not allow us to establish a sound association between non-adherence and INR values. But literature showed that, noncompliance was the cause of under-anticoagulation [13, 14]. Ensuring the patients’ understanding about the benefits of adhering to the prescribed medications and the consequences of non-adherence to treatments is crucial in order to achieve the desired therapeutic goals. Hence patient compliance can influence the frequency of long-term INR monitoring .